Imidazole derivatives for pharmaceutical use

ABSTRACT

A compound selected from the group consisting of a compound of the formula   &lt;IMAGE&gt; IA  and  &lt;IMAGE&gt; IB  having antagonist properties to histamine H3-receptors.

PRIOR APPLICATIONS

That application is a division of U.S. patent application Ser. No.117,161 filed Jan. 28, 1994, now U.S. Pat. No. 5,559,113, issued Sep,24, 1996.

The present invention relates to novel imidazole derivatives, to theirpreparation and to their therapeutic applications.

The imidazole derivatives in accordance with the invention show usefulantagonist properties for histamine H₃ receptors which control therelease and synthesis of histamine. Their antagonist activity on the H₃receptors makes them useful in therapeutics, in particular as amedicament possessing sedative, sleep regulating, anticonvulsant,psychostimulating, cerebral circulation modulating and anti-ulcereffects.

The derivatives in accordance with the invention correspond to thegeneral formula IA or IB ##STR2## in which the chain A represents asaturated or unsaturated, straight or branched hydrocarbon chaincontaining 1 to 6 carbon atoms, it being possible for the saturatedhydrocarbon chain to be interrupted by a hetero atom such as a sulphuratom,

X represents an oxygen or sulphur atom, --NH--, --NHCO--,--N(alkyl)CO--, --NHCONH--, --NH--CS--NH--, --NHCS--, --O--CO--,--CO--O--, --OCONH--, --OCON(alkyl)--, --OCONH--CO--, --CONH--,--CON(alkyl)--, --SO--, --CO--, --CHOH-- or --NR--C(═NR")--NR'--, R andR' denoting a hydrogen atom or a lower alkyl radical and R" a hydrogenatom or another powerful electronegative group, such as a cyano or COY₁group, Y₁ denoting an alkoxy group,

the chain B represents a straight alkylene chain --(CH₂)_(n) --, n beingan integer which can vary between 0 and 5 or a branched alkylene chaincontaining from 2 to 8 carbon atoms, it being possible for the alkylenechain to be interrupted by one or a number of oxygen or sulphur atoms,or a group --(CH₂)_(n) --O-- or --(CH₂)_(n) --S-- where n is an integerequal to 1 or 2,

Y represents a straight or branched alkyl group containing 1 to 8 carbonatoms, a cycloalkyl containing 3 to 6 carbon atoms, a bicycloalkylgroup, a cycloalkenyl group, an aryl group such as an optionallysubstituted phenyl group, a 5- or 6-membered heterocyclic radicalcontaining one or two heteroatoms chosen from nitrogen and sulphuratoms, the said heterocyclic radical optionally being substituted, oralso a bicyclic radical resulting from the fusion of a benzene ring to aheterocycle as defined above.

The chain A can be a straight alkylene chain --(CH₂)_(n) --, nrepresenting an integer between 0 and 6 carbon atoms, preferably between1 and 4 carbon atoms, or a branched alkylene chain, preferably a chainsubstituted by one or a number of methyl or ethyl radicals.

The chain A can also be a straight or branched alkylene chain, and canbe, for example, the allyl group.

When Y represents a cycloalkyl group, the latter can be, for example,cyclopentyl, cyclohexyl or a bicycloalkyl group.

When Y represents a substituted phenyl group, the phenyl group can bemono- or polysubstituted, for example, by a halogen, by a lower alkyl,for example CH₃, by CF₃, CN, COCH₃, COOR₁ or OR₁, R₁ representing alower alkyl, for example COOCH₃, the NO₂ group or the group NR₂ R₃, R₂and R₃ representing a hydrogen atom and/or a lower alkyl radical ("loweralkyl" means an alkyl radical containing at most 6 carbon atoms).

When Y represents a heterocyclic radical, the latter can be, forexample, the pyridyl radical, the pyridyl N-oxide radical or thepyrazinyl radical, optionally mono- or polysubstituted by NO₂, CF₃, CH₃,NH₂, a halogen such as Cl, the COOCH₃ group or also the imidazolyl orthiazolyl radical.

When Y represents a bicyclic radical resulting from the fusion of abenzene ring to a heterocycle, the radical can be, for example, thebenzothiazolyl radical.

The compounds which correspond to the formula IA or IB are novelcompounds, with the exception, however:

a) of the compounds in which X represents --NH--, the chain A the--(CH₂)₂ -- group, the chain B the --(CH₂)₂ --O-- group or the group--(CH₂)_(n) --S-- and Y the phenyl or p-chloro phenyl group,

b) of the compounds in which X represents the --NHCO-- group, the chainA the --(CH₂)₂ -- group and Y the methyl group (formula IB) or the chainB and Y (formula IA) represent a straight alkylene chain --(CH₂)_(n) --,n being between 1 and 4, the --CH₂ --O-- or --CH₂ --S--CH₂ -- groups anda phenyl group, or also the --CH₂ --CH₂ -- or --CH₂ --S--CH₂ -- groupsand the diphenyl group, or also the --(CH₂)₃ -- or --CH₂ --S--CH₂ --groups and the pyridyl group, or also the --CH₂ --CH₂ -- or --CH₂ --S--groups and the diphenyl group, or else the --(CH₂)₃ -- group and theimidazolyl or cyclohexyl group,

c) of the compounds in which X represents --NHCO--, the chain A the--CH₂ --CH(CH₂)-- group, the chain B the --(CH₂)₃ -- group and Y thephenyl group,

d) of the compounds in which X represents --NHCSNH-- or --NHCONH--, thechain A the --(CH₂)₂ -- group, the chain B the --(CH₂)₂ -- group and Ythe phenyl group,

e) of the compounds in which the chain A represents a straight saturatedhydrocarbon chain containing 1 to 6 carbon atoms, X represents --NH--,the chain B represents an alkylene chain as defined above and Yrepresents a phenyl group or an imidazolyl radical, as well as those inwhich A represents a straight saturated hydrocarbon chain containing 1to 6 carbon atoms, X represents the --NHCONH-- group, the chain B and/orY represent an alkyl and Y represents an aryl radical;

f) of the compounds in which X represents an oxygen atom, the chain A a--CH₂ -- group and Y a substituted phenyl group (formula IB);

g) of the compounds in which X represents the --NHCO-- group, the chainA the --(CH₂)₂ -- group and Y a substituted cyclohexyl group (formulaIB);

h) of the compounds in which X represents the --NH--CS--NH-- group, thechain A the group --(CH₂)_(n) --(n=3 to 6) and Y an alkyl, aryl andaralkyl group (formula IB);

i) of the compounds in which X represents the --CO-- group, the chain Athe --(CH₂)₂ -- group and Y an optionally substituted aryl radical, a5-membered heterocyclic radical containing sulphur as heteroatom andoptionally substituted, or a bicyclic radical resulting from the fusionof a benzene ring to a 5--or 6-membered heterocycle containing nitrogenand/or sulphur atoms as hetero atoms (formula IB);

j) of the compounds in which X represents the --CONH-- group, the chainA the --(CH₂)₂ -- group and Y the optionally substituted phenyl group(formula IB);

k) of the compounds in which X represents the --NH--C(═NCN)--NH-- group,the chain A a hydrocarbon chain containing 2 to 4 C atoms interrupted byan S atom and Y a 5- or 6-membered heterocycle containing one or twonitrogen and sulphur atoms (formula IB);

l) of the compounds in which X represents the --NH--C(═NCN)--NH-- group,the chain A a --CH₂ --S--(CH₂)₂ -- group and Y a methyl radical (formulaIB);

m) of the compounds in which X represents the --NH--C(═NH)--NH-- group,the chain A and chain B have the abovementioned meaning and Y representsan alkyl group, an aryl group, or a 5- or 6-membered heterocyclicradical containing one or two heteroatoms which can be nitrogen and/orsulphur.

The compounds set out under a) to d) were disclosed during a symposiumwhich was held at Budapest in August 1988 ("10th International Symposiumon Medicinal Chemistry") and more recently at Noordwijkerhout (July1990).

The compounds set out under e) have been described in Patent GB1,341,375; the compounds set out under f) in French patent No.1,220,002; the compounds set out under g) in U.S. Pat. No. 2,301,532 and2,376,424; the compounds set out under h) in Patent GB 1,305,547; thecompounds set out under i) in European Patent ApplicationEP-A-0,291,172; the compounds set out under j) in European PatentApplication EP-A-315,316; the compounds set out under k) in Patent GB1,531,221 and the compounds set out under 1) in Australian PatentAU-A-514,574; the compounds set out under m) in European PatentApplications EP-A-0,199,845 and EP-A-0,262,448.

The present invention also relates to the addition salts which thecompounds of formula IA or IB form with pharmaceutically acceptableacids. The pharmaceutically acceptable salts comprise the nontoxic saltsof inorganic or organic acids such as the hydrochloride, thehydrobromide or the maleate.

The present invention also encompasses the hydrates of the compounds offormula IA or IB, the hydrated salts of these compounds and thepolymorphic crystalline structures. It is necessary, moreover, to notethat the structure of the compounds in accordance with the invention, asit is illustrated by the formulae IA and IB, only represents one of thepossible tautomeric forms of these compounds and that the latter canexist under other tautomeric forms. The present invention thus alsoencompasses all the possible tautomeric forms of the compounds inquestion, whether these tautomers exist in the isolated form or in theform of mixtures.

The compounds of formula IA or IB can exist in one or a number ofisomeric forms according to the number of asymmetric centres in themolecule. The invention thus relates both to all the optical isomers andto their racemic modifications and the corresponding diastereoisomers.The separation of the diastereoisomers and/or of the optical isomers canbe carried out according to methods known per se.

The compounds of formula IA or IB in which X represents --NH--, thechain A, the chain B and Y having the abovementioned meanings, areobtained, for example, by reacting an amine of formula ##STR3## with ahalogenated compound of formula

    Hal-(chain B)--Y

or

    Hal--Y

Hal denoting a halogen such as chlorine or bromine, in the presence of asolvent.

The compounds of formula IA or IB in which X represents --NHCO--, thechain A, the chain B and Y having the abovementioned meanings, areobtained, for example, by reacting an amine of formula ##STR4## with anacid of formula

    HOOH--(chain B)--Y

or

    HOOH--Y

after optional activation of the hydroxyl functional group of this acid.

The compounds of formula IA in which X represents --NH-- andcorresponding to the general formula ##STR5## the chain A, Y and nhaving the abovementioned meanings, can also be obtained by reducing thecarbonyl group in the compound of formula ##STR6## for example using ahydride such as sodium borohydride.

The compounds of formula IA in which X represents --NH--, the chain Brepresents --(CH₂)_(n) --S--, n being between 1 and 4, the chain A and Yhaving the abovementioned meanings, are obtained by treating a compoundof formula ##STR7## with a halogenated hydracid, such as hydrobromicacid, to form the halogenated compound ##STR8## Hal denoting a halogen,and by reacting a compound of formula

    HS--Y

with this halogenated compound.

The compounds of formula IA or IB in which X represents --NHCS--, thechain A, the chain B and Y having the abovementioned meanings, can beobtained by treating a compound of formula ##STR9## with asulphurization agent in the presence of a solvent such as pyridine.

The compounds of formula IA or IB in which X represents --NHCONH-- or--NHCSNH--, the chain A, the chain B and Y having the abovementionedmeanings, can be obtained by reacting an amine, provided, for example,in the dihydrochloride form of formula ##STR10## with an isocyanate offormula

    OCN--(chain B)--Y

or

    OCN--Y

or an isothiocyanate of formula

    SCN--(chain B)--Y

or

    SCN--Y

in the presence of a nonpolar solvent.

The compounds of formula IA or IB in which X represents --OCO--, thechain A, the chain B and Y having the abovementioned meanings, can beobtained by reacting an acid chloride of formula

    ClCO--(chain B)--Y

or

    ClCO--Y

on an alcohol, provided, for in example, in the hydrochloride form, offormula ##STR11## in the presence of a solvent such as pyridine.

The compounds of formula IA or IB in which X represents --CO--O--, thechain A, the chain B and Y having the abovementioned meanings, can beobtained by reacting an acid of formula ##STR12## with an alcohol offormula

    HO--(chain B)--Y

or

    HO--Y

in the presence of thionyl chloride.

The compounds of formula IA or IB in which X represents --OCONH--, thechain A, the chain B and Y having the abovementioned meanings, can beobtained by reacting an alcohol, provided, for example, in thehydrochloride form, of formula ##STR13## with an isocyanate of formula

    OCN--(chain B)--Y

or

    OCN--Y

in the presence of a nonpolar solvent.

The compounds of formula IA or IB in which X represents --O--, the chainA, the chain B and Y having the abovementioned meanings, can be obtainedby reacting an alkoxide of formula ##STR14## Phe denoting the phenylradical, with a halogenated compound of formula

    Hal-(chain B)--Y

or

    Hal--Y

Hal denoting a halogen, in the presence of a neutral solvent such astoluene, and then cleaving the --C(Phe)₃ group with an acid solution.

The compounds of formula IA or IB in which X represents --O--, the chainA, the chain B and Y having the abovementioned meanings, can also beobtained by reacting a halogenated compound, provided, for example, inthe hydrochloride form, of formula ##STR15## Hal denoting a halogen suchas chlorine, with an alcohol of formula

    HO--(chain B)--Y

or

    HO--Y.

The compounds of formula IB in which X represents --O--, the chain A hasthe abovementioned meaning and Y represents an optionally substitutedphenyl group can also be obtained by reacting an alcohol of formula##STR16## with a phenolic compound of formula ##STR17## in which Rrepresents a substituent such as a halogen, a lower alkyl, CF₃, CN orCOCH₃, in the presence of triphenylphosphine and of diethylazodicarboxylate in a solvent and by cleaving the --C(Phe)₃ group bytreatment with an acid solution.

The compounds of formula IA or IB in which X represents --S--, the chainA, the chain B and Y having the abovementioned meanings, can be obtainedby reacting an isothiourea of formula ##STR18## with a halogenatedcompound of formula

    Hal-(chain B)--Y

or

    Hal--Y

Hal denoting a halogen such as chlorine, in the presence of a solventsuch as ethanol.

The compounds of formula IA or IB in which X represents --S--, the chainA, the chain B and Y having the abovementioned meanings, can also beobtained by reacting an alcohol of formula ##STR19## with a compound offormula

    HS--(chain B)--Y

or

    HS--Y

in the presence of a halogenated hydracid such as hydrobromic acid or byreacting a halogenated compound of formula ##STR20## Hal denoting ahalogen, with a compound of formula

    HS--(chain B)--Y

or

    HS--Y

in the presence of a base such as an alkaline hydroxide.

The compounds of formula IA or IB in which X represents --SO--, thechain A, the chain B and Y having the abovementioned meanings, can beobtained by treating a compound of formula ##STR21## with a base such asan alkali metal or alkaline-earth metal hydroxide or carbonate in thepresence of a solvent and then with an oxidizing agent.

The compounds of formula IA or IB in which X represents --CO--, thechain A, the chain B and Y having the abovementioned meanings, can beobtained by reacting a compound of formula ##STR22## Phe denoting thephenyl radical, with

    Hal-Mg--(chain B)--Y

or

    Hal-Mg--Y

Hal denoting a halogen, in the presence of a solvent, and then byhydrolysis of the product obtained.

The compounds of formula IA or IB in which X represents --CHOH--, thechain A, the chain B and Y having the abovementioned meanings, can beobtained by reducing the compound of formula ##STR23## for example witha hydride, in the presence of a solvent, and then by hydrolysis with abasic solution.

The compounds of formula IA or IB in which X represents--NR--C(═NR")--NR'--, R, R', R", the chain A, the chain B and Y havingthe abovementioned meanings, can be obtained by reacting a compound offormula ##STR24## with an amine of formula

    H.sub.2 N--R'--(chain B)--Y

or

    H.sub.2 N--R'--Y

to form a compound of formula ##STR25## and by reacting the lattercompound with an amine of formula ##STR26## to form the compound offormula ##STR27## and, when R" represents hydrogen, by treating thelatter compound with an acid solution to form the compound of formula##STR28##

The examples which are given below, as non-limiting, illustrate thepresent invention.

EXAMPLE 1

N--((1H-Imidazol-4-yl)methyl)-5-phenylpentanamide

8 mmol of N,N'-carbonyldiimidazole and 8 mmol of 5-phenylpentanoic acidare introduced successively into 10 ml of absolute THF and, after havingstirred for 30 min, 8 mmol of (1H-imidazol-4-yl)methanamine are added tothe mixture, moisture being excluded using CaCl₂. At the end of 14 h,the solvent is removed by distilling under vacuum. The remaining oil ismixed with a small amount of water. The title compound is filtered undervacuum, dried and crystallized from ethanol/diethyl ether.

C₁₅ H₁₉ N₃ O (257.4) M.p.: 125°-137° C. Yield:35%

Elemental analysis: calculated: C 70.0 H 7.44 N 16.3 found: C 70.0 H7.52 N 16.3

EXAMPLE 2

N-(3-(1H-Imidazol-4-yl)propyl)-3-phenylpropanamide

The preparation is carried out as in Example 1 with 10 mmol of3-phenylpropanoic acid and 3-(1H-imidazol-4-yl)propanamine as the aminecomponent. The title compound is purified by chromatography andrecrystallized in the hydrogenmaleate forth from ethyl acetate/acetonitrile.

C₁₅ H₁₉ N₃ O C₄ H₄ O₄ (375.4) M.p.: 126°-127° C. Yield: 70%

Elemental analysis: calculated: C 60.8 H 6.71 N 11.2 found: C 61.0 H6.30 N 11.1

EXAMPLE 3

N-(3-(1H-Imidazol-4-yl)propyl)-3-cyclohexylpropanamide

The preparation is carried out as in Example 2 with3-cyclohexylpropanoic acid. The title compound is purified bychromatography and recrystallized from ethanol/diethyl ether.

C₁₅ H₂₅ N₃ O (379.5) M.p.: 119° C. yield: 50%

Elemental analysis: calculated: C 60.1 H 7.70 N 11.1 found: C 60.2 H8.01 N 11.0

EXAMPLE 4

N-(3-(1H-Imidazol-4-yl)propyl)-3-cyclopentylpropanamide

The preparation is carried out as in Example 2 with3-cyclopentylpropanoic acid. The title compound is purified bychromatography and precipitated in the hydrogenmaleate form fromethanol/diethyl ether.

C₁₄ H₂₃ N₃ O. C₄ H₄ O₄ (365.4) M.p.: 106° C. yield: 40%

Elemental analysis: calculated: C 59.2 H 7.45 N 11.5 found: C 59.0 H7.68 N 11.7

EXAMPLE 5

N-(3-(1H-Imidazol-4-yl)propyl)-2-(4-chlorophenoxy)acetamide

The preparation is carried out as in Example 2 with4-chlorophenoxyacetic acid. The title compound is extracted with diethylether and precipitated in the hydrogenmaleate form from ethanol/diethylether.

C₁₄ H₁₆ N₃ O₂ Cl.C₄ H₄ O₄.0.5H₂ O (418.8) M.p.: 141° C. yield: 70%

Elemental analysis: calculated: C 51.6 H 5.05 N 10.0 found: C 51.6 H5.15 N 10.2

EXAMPLE 6

N-(3-(1H-Imidazol-4-yl)propyl)-2-cyclohexylacetamide

The preparation is carried out as in Example 2 with cyclohexylaceticacid. The title compound is filtered under vacuum, dried andrecrystallized in the hydrogenmaleate form from ethanol/diethyl ether.

C₁₄ H₂₃ N₃ O.C₄ H₄.0.5H₂ O (374.4) M.p.: 122° C. yield: 40%

Elemental analysis: calculated: C 57.7 H 7.54 N 11.2 found: C 58.1 H7.38 N 11.3

EXAMPLE 7

N-(3-(1H-Imidazol-4-yl)propyl)-4-cyclohexylbutanamide

The preparation is carried out as in Example 2 with 4-cyclohexylbutanoicacid. The title compound is purified by chromatography andrecrystallized in the hydrogenmaleate form from ethanol/diethyl ether.

C₁₆ H₂₇ N₃ O.C₄ H₄ O₄.0.5H₂ O (402.5) M.p.: 86° C. yield 55%

Elemental analysis: calculated: C 59.7 H 8.01 N 10.4 found: C 59.5 H7.85 N 10.4

EXAMPLE 8

N-(3-(1H-Imidazol-4-yl)propyl)-4-methylpentanamide

The preparation is carried out as in Example 2 with 4-methylpentanoicacid. The title compound is purified by chromatography andrecrystallized in the hydrogenmaleate form from ethanol/diethyl ether.

C₁₂ H₂₁ N₃ O. C₄ H₄ O₅.0.5H₂ O (348.4) M.p.: 115° C. yield: 40%

Elemental analysis: calculated: C 55.2 H 7.52 N 12.1 found: C 55.4 H7.57 N 12.1

EXAMPLE 9

N-(3-(1H-Imidazol-4-yl)propyl)-3,3-diphenylpropanamide

The preparation is carried out as in Example 2 with3,3-diphenylpropanoic acid. The title compound is purified bychromatography and recrystallized in the hydrogenmaleate form fromethanol/diethyl ether.

C₂₁ H₂₃ N₃ O. C₄ H₄ O₄ (449.5) M.p.: 116° C. yield 65%

Elemental analysis: calculated: C 66.8 H 6.05 N 9.35 found: C 66.7 H6.03 N 9.36

EXAMPLE 10

N-(3-(1H-Imidazol-4-yl)propyl)-3-(bicyclo 2.2.1!hept-2-yl)propanamide

The preparation is carried out as in Example 2 with 3-(bicyclo2.2.1!hept-2-yl)propanoic acid. The title compound is purified bychromatography and recrystallized in the hydrogenmaleate form fromethanol/diethyl ether.

C₁₆ H₂₃ N₃ O.C₄ H₄ O₄.0.5H₂ O (398.5) M.p.: 112° C. yield 35%

Elemental analysis: calculated: C 60.3 H 7.08 N 10.6 found: C 60.1 H7.46 N 10.6

EXAMPLE 11

N-(3-(1H-Imidazol-4-yl)propyl)hexanamide

The preparation is carried out as in Example 2 with hexanoic acid. Thetitle compound is purified by chromatography and recrystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₂ H₂₁ N₃ O. C₄ H₄ O₄.0.5H₂ O (348.4) M.p.: 69° C. yield 45%

Elemental analysis: calculated: C 55.2 H 7.52 N 12.1 found: C 55.2 H7.46 N 12.0

EXAMPLE 12

N-(3-(1H-Imidazol-4-yl)propyl)heptanamide

The preparation is carried out as in Example 2 with heptanoic acid. Thetitle compound is purified by chromatography and recrystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₃ H₂₃ N₃ O. C₄ H₄ O₄ (353.4) M.p.: 73°-74° C. yield 50%

Elemental analysis: calculated: C 57.8 H 7.70 N 11.9 found: C 57.5 H8.00 N 11.8

EXAMPLE 13

N-(3-(1H-Imidazol-4-yl)propyl)octanamide

The preparation is carried out as in Example 2 with octanoic acid. Thetitle compound is purified by chromatography and recrystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₄ H₂₅ N₃ O.C₄ H₄ O₄ (367.4) M.p.: 74° C. yield 50%

Elemental analysis: calculated: C 58.8 H 7.95 N 11.4 found: C 58.6 H8.00 N 11.3

EXAMPLE 14

N-(3-(1H-Imidazol-4-yl)propyl)-3-(2-cyclopenten-1H-yl)propanamide

The preparation is carried out as in Example 2 with3-(2-cyclopenten-1-yl)propanoic acid. The title compound is purified bychromatography and recrystallized in the hydrogenmaleate form fromethanol/diethyl ether.

C₁₄ H₂₁ N₃ O.C₄ H₄ O₄.0.5H₂ O (372.4) M.p.: 84° C. yield 45%

Elemental analysis: calculated: C 58.1 H 7.04 N 11.3 found: C 58.2 H6.84 N 11.7

EXAMPLE 15

(R,S)-(+)-N-(3-(1H-Imidazol-4-yl)propyl)-3-phenylbutanamide

The preparation is carried out as in Example 2 with 3-phenylbutanoicacid. The title compound is purified by chromatography andrecrystallized in the hydrogenmaleate form from ethanol/diethyl ether.

C₁₆ H₂₁ N₃ O.C₄ H₄ O₄.0.25H₂ O (391.9) M.p.: 89° C. yield 65%

Elemental analysis: calculated: C 61.3 H 6.55 N 10.7 found: C 61.3 H6.52 N 10.8

EXAMPLE 16

N-(3-(1H-Imidazol-4-yl)propyl)-3-(2-pyrazinyl)propanamide

The preparation is carried out as in Example 2 with3-(2-pyrazinyl)propanoic acid. The title compound is purified bychromatography and recrystallized in the hydrogenmaleate form fromethanol/diethyl ether.

C₁₃ H₁₇ N₅ O. 2HCl. H₂ O (350.2) M.p.: 150° C. yield 25%

Elemental analysis: calculated: C 44.6 H 6.04 N 20.0 found: C 44.9 H5.68 N 20.3

EXAMPLE 17

N-(4-(1H-Imidazol-4-yl)butyl)-2-cyclopentylacetamide

The preparation is carried out as in Example 1 with 2-cyclopentylaceticacid and 4-(1H-imidazol-4-yl)butanamine. The title compound is extractedfrom water with diethyl ether and recrystallized in the hydrogenmaleateform from ethanol/diethyl ether.

C₁₄ H₂₃ N₃ O.C₄ H₄ O₄ (374.4) M.p.: 114° C. yield 65%

Elemental analysis: calculated: C 59.2 H 7.45 N 11.5 found: C 58.8 H7.78 N 11.5

EXAMPLE 18

N-(4-(1H-Imidazol-4-yl)butyl)-3-cyclopentylpropanamide

The preparation is carried out as in Example 17 with3-cyclopentylpropanoic acid. The title compound is extracted from waterwith diethyl ether and recrystallized in the hydrogenmaleate form fromethanol/diethyl ether.

C₁₅ H₂₅ N₃ O.C₄ H₄ O₄.H₂ O (397.5) M.p.: 124° C. yield 65%

Elemental analysis: calculated: C 57.4 H 7.86 N 10.6 found: C 57.6 H7.48 N 10.2

EXAMPLE 19

(E)-N-(3-(1H-Imidazol-4-yl)allyl)-3-cyclopentylpropanamide

The preparation is carried out as in Example 4 with(E)-3-(1H-imidazol-4-yl)allylamine as amine component. The titlecompound is extracted from water with The title compound is extractedfrom water with diethyl ether and recrystallized in the hydrogenmaleateform from ethanol/diethyl ether.

C₁₄ H₂₁ N₃ O.C₄ H₄ O₄.0.5H₂ O (372.4) M.p.: 156° C. yield 70%

Elemental analysis: calculated: C 58.1 H 7.04 N 11.3 found: C 58.1 H6.88 N 11.3

EXAMPLE 20

N-(3-Phenylpropyl)-3-(1H-imidazol-4-yl)propanamide

The preparation is carried out as in Example 1 with 3-phenylpropanamineand 3-(1H-imidazol-4-yl)propanoic acid, the acid being here added afterthe reaction of the amine component with N,N'-carbonyldiimidazole. Thetitle compound is extracted from water with diethyl ether, purified bychromatography and recrystallized in the hydrogenmaleate form fromethanol/diethyl ether.

C₁₅ H₁₉ N₃ O.C₄ H₄ O₄.0.5H₂ O (382.4) M.p.: 116° C yield 45%

Elemental analysis: calculated: C 59.7 H 6.33 N 11.0 found: C 59.8 H6.09 N 10.8

EXAMPLE 21

N-(2-(1H-Imidazol-4-yl)ethyl)-4-cyclohexylbutanethioamide

First of all N-(2-(1H-imidazol-4-yl)ethyl)-4-cyclohexylbutanamide isprepared by reacting 10 mmol of 4-cyclohexylbutanoic acid and2-(1H-imidazol-4-yl)ethylamine. The compound obtained is filtered undervacuum, dried and recrystallized from ethanol/diethyl ether.

3 mmol of the latter compound are maintained for 1 h at reflux in 5 mlof phosphorus pentasulphide in 20 ml of pyridine. After evaporationunder vacuum, the residue is taken up in a water/chloroform mixture,brought to a pH of 9 with aqueous ammonia and washed 3 times with water.The organic phase is concentrated and purified by chromatography. Thetitle compound obtained is recrystallized from ethanol/diethyl ether.

C₁₅ H₂₅ N₃ S (279.5) M.p.: 82° C. yield: 50%

Elemental analysis: calculated: C 64.5 H 9.02 N 15.0 found: C 64.1 H9.17 N 14.7

EXAMPLE 22

N-(3-(1H-Imidazol-4-yl)propyl)-3-cyclopentylpropanethioamide

The preparation is carried out as in Example 21, starting with thecompound obtained in Example 4. The title compound is recrystallized inthe hydrogenmaleate form from ethanol/diethyl ether.

C₁₄ H₂₃ N₃ S.C₄ H₄ O₄.H₂ O (399.5) M.p.: 91°-92° C. yield: 25%

Elemental analysis: calculated: C 54.1 H 7.31 N 10.5 found: C 54.3 H6.96 N 10.5

EXAMPLE 23

N-Benzyl-N'-(3-(1H-imidazol-4-yl)propyl)urea

5 mmol of 3-(1H-imidazol-4-yl)propanamine dihydrochloride and 10 mmol oftriethylamine are mixed in 10 ml of acetonitrile and, after addition of5 mmol of benzyl isocyanate, the whole mixture is brought to boiling for1 h at reflux. After evaporation under vacuum, the title compound istaken up in a small amount of water and recrystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₄ H₁₈ N₄ O.C₄ H₄ O₄ (374.4) M.p.: 119° C. yield: 80%

Elemental analysis: calculated: C 57.7 H 5.92 H 15.0 found: C 57.7 H6.05 H 14.6

EXAMPLE 24

3-(1H-Imidazol-4-yl)propyl ester of 3-cyclopentylpropanoic acid

5 mmol of 3-(1H-imidazol-4-yl)propanol hydrochloride in 30 ml ofpyridine with 10 mg of 4-dimethylaminopyridine are added to 5 mmol ofthe chloride of 3-cyclopentylpropanoic acid and the whole mixture isstirred for 16 h at room temperature. The solution is evaporated undervacuum, the residue is then taken up in water and extracted with diethylether. A hydrogenmaleate is formed from the oil obtained, decolouredwith active charcoal and recrystallized from ethanol/diethyl ether.

C₁₄ H₂₂ N₂ O₂.C₄ H₄ O₄ (366.4) M.p.: 88° C. yield: 30%

Elemental analysis: calculated: C 59.0 H 7.15 N 7.65 found: C 59.0 H7.39 N 7.65

EXAMPLE 25

3-(1H-Imidazol-4-yl)propyl ester of benzoic acid

The preparation is carried out as in Example 24 with the chloride ofbenzoic acid. The title compound is crystallized in the hydrogenmaleateform from ethanol/diethyl ether.

C₁₃ H₁₄ N₂ O₂.C₄ H₄ O₄.0.5H₂ O (355.4) M.p.: 165° C. yield: 75%

Elemental analysis: calculated: C 57.5 H 5.39 N 7.88 found: C 57.1 H5.07 N 7.95

EXAMPLE 26

3-(1H-Imidazol-4-yl)propyl ester of 4-iodobenzoic acid

The preparation is carried out as in Example 24 with the chloride of4-iodobenzoic acid. The title compound is crystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₃ H₁₃ N₂ O₂ I.C₄ H₄ O₄.0.5H₂ O (481.2) M.p.: 148° C. yield: 60%

Elemental analysis: calculated: C 42.4 H 3.77 N 5.82 found: C 42.5 H3.52 N 5.89

EXAMPLE 27

3-(1H-Imidazol-4-yl)propyl ester of 3-iodobenzoic acid

The preparation is carried out as in Example 24 with the chloride of3-iodobenzoic acid. The title compound is crystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₃ H₁₃ N₂ O₂ I.C₄ H₄ O₄.0.25H₂ O (481.2) M.p.: 105° C. yield: 70%

Elemental analysis: calculated: C 42.4 H 3.77 N 5.82 found: C 42.3 H3.52 N 5.78

EXAMPLE 28

3-(1H-Imidazol-4-yl)propyl ester of 3-iodo-4-methylbenzoic acid

The preparation is carried out as in Example 24 with the chloride of3-iodo-4-methylbenzoic acid. The title compound is crystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₄ H₁₅ N₂ O₂ I.C₄ H₄ O₄ (486.3) M.p.: 112°-133° C. yield: 70%

Elemental analysis: calculated: C 44.5 H 3.94 N 5.76 found: C 44.5 H4.09 N 5.88

EXAMPLE 29

3-(1H-Imidazol-4-yl)propyl ester of 3-(4-iodophenyl)propanoic acid

The preparation is carried out as in Example 24 with the chloride of3-(4-iodophenyl)propanoic acid. The title compound is crystallized inthe hydrogenmaleate form from ethanol/diethyl ether.

C₁₅ H₁₇ N₂ O₂ I.C₄ H₄ O₄ (500.29) M.p.: 147° C. yield: 80%

Elemental analysis: calculated: C 45.6 H 4.23 N 5.60 found: C 45.9 H4.29 N 5.68

EXAMPLE 30

3-(1H-Imidazol-4-yl)propyl ester of 4-amino-3,5-diiodobenzoic acid

The preparation is carried out as in Example 24 with the chloride of4-amino-3,5-diiodobenzoic acid. The title compound is crystallized inthe hydrogenmaleate form from ethanol/diethyl ether.

C₁₃ H₁₃ N₃ O₂ I₂.C₄ H₄ O₄ (613.2) M.p.: 155° C. yield: 75%

Elemental analysis: calculated: C 33.3 H 2.79 N 6.85 found: C 33.1 H2.60 N 6.83

EXAMPLE 31

3-(1H-Imidazol-4-yl)propyl ester of 4-(4-iodophenyl)butanoic acid

The preparation is carried out as in Example 24 with the chloride of4-(4-iodophenyl)butanoic acid. The title compound is crystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₆ H₁₉ N₂ O₂ I.C₄ H₄ O₄ (514.3) M.p.: 126° C. yield: 80%

Elemental analysis: calculated: C 46.7 H 4.51 N 5.45 found: C 46.7 H4.65 N 5.31

EXAMPLE 32

3-(1H-Imidazol-4-yl)propyl ester of 2-(4-iodophenyl)acetic acid

The preparation is carried out as in Example 24 with the chloride of2-(4-iodophenyl)acetic acid. The title compound is crystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₄ H₁₅ N₂ O₄ I.C₄ H₄ O₄ (486.3) M.p.: 88° C. yield: 60%

Elemental analysis: calculated: C 44.5 H 3.93 N 5.76 found: C 44.7 H3.99 N 5.55

EXAMPLE 33

3-(1H-Imidazol-4-yl)propyl ester of 4-phenylbutanoic acid

The preparation is carried out as in Example 24 with the chloride of4-phenylbutanoic acid. The title compound is crystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₆ H₂₀ N₂ O₂.C₄ H₄ O₄.0.5H₂ O (397.4) M.p.: 88° C. yield: 60%

Elemental analysis: calculated: C 60.4 6.34 N 7.05 found: C 60.6 6.19 N7.20

EXAMPLE 34

3-(1H-Imidazol-4-yl)propyl N-benzylcarbamate

The preparation is carried out as in Example 23 with3-(1H-imidazol-4-yl)propanol hydrochloride and 5 mmol of triethylamine.The residual oil is taken up in a small amount of water. The titlecompound is crystallized in the hydrogenmaleate form fromethanol/diethyl ether.

C₁₄ H₁₇ N₃ O₂.C₄ H₄ O₄ (375.4) M.p.: 123° C. yield: 90%

Elemental analysis: calculated: C 57.6 H 5.64 N 11.2 found: C 57.2 H5.63 N 11.2

EXAMPLE 35

3-(1H-Imidazol-4-yl)propyl N-(cyclohexylmethyl)carbamate

The preparation is carried out as in Example 34 with sodium3-(1H-imidazol-4-yl)propoxide. The residual oil is taken up in a smallamount of water. The title compound is filtered under vacuum, dried andrecrystallized in the hydrogenmaleate form from ethanol/ diethyl ether.

C₁₄ H₂₃ N₃ O₂.C₄ H₄ O₄ (381.4) M.p.: 106° C. yield: 40%

Elemental analysis: calculated: C 56.7 H 7.13 N 11.0 found: C 56.3 H7.33 N 11.0

EXAMPLE 36

3-Cyclohexylpropyl 3-(1H-imidazol-4-yl)propyl ether

5 mmol of sodium 3- 1-(triphenylmethyl)imidazol-4-yl!propoxide in 10 mlof toluene containing 0.5 mmol of 15-Crown-5 and 5 mmol of(3-chloropropyl)cyclohexane are mixed and the mixture is stirred for 24h at 75° C. The suspension is concentrated under vacuum, the productobtained is dissolved in diethyl ether, the solution is filtered and theresidue washed with petroleum ether (40°-60° C.). The filtrate obtainedis concentrated and maintained for 1 h at the boiling point in a 2Naqueous/alcohol (ethanol/water) hydrochloric acid solution. The ethanolis removed under a low vacuum and the precipitate is filtered undervacuum. The solution is basified, extracted with dichloromethane and theorganic phase is concentrated. The title compound obtained isrecrystallized in the hydrogenmaleate form from ethanol/ diethyl ether.

C₁₅ H₂₆ N₂ O.C₄ H₄ O₄.0.25H₂ O (370.9) M.p.: 114°-116° C. yield: 35%

Elemental analysis: calculated: C 61.52 H 8.29 N 7.55 found: C 61.60 H8.25 N 7.50

EXAMPLE 37

3-(3,4-Difluorophenyl)propyl 3-(1H-imidazol-4-yl)propyl ether

The preparation is carried out as in Example 36 with3-(3,4-difluorophenyl)propyl chloride. The title compound iscrystallized in the hydrogenmaleate form from ethanol/diethyl ether.

C₁₅ H₁₈ N₂ OF₂.C₄ H₄ O₄ (396.4) M.p.: 101° C. yield: 25%

Elemental analysis: calculated: C 57.6 H 5.59 N 7.07 found: C 57.4 H5.52 N 7.14

EXAMPLE 38

3-(4-Bromophenyl)propyl 3-(1H-imidazol-4-yl)propyl ether

The preparation is carried out as in Example 36 with3-(4-bromophenyl)propyl chloride. The title compound is crystallized inthe hydrogenmaleate form from ethanol/ diethyl ether.

C₁₅ H₁₉ N₂ OBr.C₄ H₄ O₄ (439.3) M.p.: 130°-131° C. yield: 35%

Elemental analysis: calculated: C 52.0 H 5.28 N 6.38 found: C 52.4 H5.35 N 6.57

EXAMPLE 39

3-(3-Trifluoromethylphenyl)propyl 3-(1H-imidazol-4-yl)propyl ether

The preparation is carried out as in Example 36 with3-(3-trifluoromethylphenyl)propyl chloride. The title compound iscrystallized in the hydrogenmaleate form from ethanol/diethyl ether.

C₁₆ H₁₉ N₂ OF₃.C₄ H₄ O₄ (428.4) M.p.: 85° C. yield: 35%

Elemental analysis: calculated: C 56.1 H 5.41 N 6.54 found: C 55.9 H5.44 N 6.48

EXAMPLE 40

1-Naphthylmethyl 3-(1H-imidazol-4-yl)propyl ether

The preparation is carried out as in Example 36 with 1-naphthylmethylchloride. The title compound is crystallized in the hydrogenmaleate formfrom ethanol/diethyl ether.

C₁₇ H₁₈ N₂ O.C₄ H₄ O₄.0.25H₂ O (386.9) M.p.: 75° C. yield: 40%

Elemental analysis: calculated: C 65.2 H 5.86 N 7.24 found: C 65.3 H5.71 N 6.93

EXAMPLE 41

(4-Iodophenyl)methyl 3-(1H-imidazol-4-yl)propyl ether

The preparation is carried out as in Example 36 with(4-iodophenyl)methyl chloride. The title compound is crystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₃ H₁₅ N₂ OI.C₄ H₂ O₄.0.5H₂ O (467.3) M.p.: 123°-124° C. yield: 25%

Elemental analysis: calculated: C 43.7 H 4.31 N 5.99 found: C 43.6 H3.94 N 5.99

EXAMPLE 42

4-Phenylbutyl 3-(1H-imidazol-4-yl)propyl ether

The preparation is carried out as in Example 36 with 4-phenylbutylchloride. The title compound is crystallized in the hydrogenmaleate formfrom ethanol/diethyl ether.

C₁₆ H₂₂ N₂ O.C₄ H₄ O₄ (374.4) M.p.: 96° C. yield: 40%

Elemental analysis: calculated: C 64.2 H 7.00 N 7.48 found: C 63.9 H7.09 N 7.69

EXAMPLE 43

(Z)-N-(3-(1H-Imidazol-4-yl)allyl)-3-cyclohexylpropanamide

The preparation is carried out as in Example 3 with(Z)-3-(1H-imidazol-4-yl)allylamine. The title compound is extracted fromwater with diethyl ether and is precipitated in the hydrogenmaleate formfrom ethanol/diethyl ether.

C₁₄ H₂₁ N₃ O.C₄ H₄ O₄.0.5H₂ O (372.4) M.p.: 134° C. yield: 65%

Elemental analysis: calculated: C 58.1 H 7.04 N 11.3 found: C 58.1 H6.88 N 11.3

EXAMPLE 44

(R,S)-(±)-N-(3-(1H-Imidazol-4-yl)butyl)-3-cyclohexylpropanamide

The preparation is carried out as in Example 3 with(R,S)-(±)-3-(1H-imidazol-4-yl)butanamine. The title compound isextracted from water with dichloromethane and precipitated in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₆ H₂₇ N₃ O.C₄ H₄ O₄.0.5H₂ O (393.5) M.p.: 79° C. yield: 30%

Elemental analysis: calculated: C 59.7 H 8.01 N 10.4 found: C 59.8 H7.66 N 10.5

EXAMPLE 45

3-Phenylpropyl 3-(1H-imidazol-4-yl)propyl ether

The preparation is carried out as in Example 36 with 3-phenylpropylbromide. The title compound obtained is recrystallized in thehydrogenmaleate form from ethanol/ether.

C₁₅ H₂₀ N₂ O.C₄ H₄ O₄..0.25H₂ O (364.9) M.p.: 103° C. yield: 40%

Elemental analysis: calculated: C 62.5 H 6.77 N 6.88 found: C 62.4 H6.78 N 6.83

EXAMPLE 46

3-Phenylpropyl 3-(1H-imidazol-4-yl)propyl sulphide

5mmol of 3-(1H-imidazol-4-yl)propyl chloride are introduced into asolution of 6 mmol of 3-phenylpropanethiol and 10 mmol of sodium in 30ml of ethanol and the mixture is brought to reflux for 3 h. Thesuspension is evaporated under vacuum until dryness, potassium carbonateis added and the mixture is stirred in methanol/water. The residualsemi-solid oil is brought to boiling in ethanol with active charcoal,filtered and recrystallized in the hydrogenmaleate form fromethanol/diethyl ether.

C₁₅ H₂ N₂ S.C₄ H₄ O₄.0.5H₂ O (385.5) M.p.: 106° C. yield: 35%

Elemental analysis: calculated: C 59.2 H 6.54 N 7.27 found: C 59.3 H6.38 N 7.30

EXAMPLE 47

4- (4-Nitrobenzylthio)methyl!-1H-imidazole

A mixture of 1.53 g (10 mmol) of 4-chloromethylimidazole hydrochlorideand 0.76 g (10 mmol) of thiourea is brought to reflux in 10 ml ofethanol for 15 min. 5 ml of ethanol, 20 ml of water and 200 mg (1.16mmol) of 4-nitrobenzyl chloride are added and the mixture is cooled to0°-10° C. 1.44 g (36 mmol) of a solution of sodium hydroxide in 14 ml ofwater are added dropwise under nitrogen at 0°-10° C., and the mixture isthen stirred for 1 hour at the same temperature and for a further 3hours at room temperature. The abovementioned is collected and washedwith water to provide the title compound, M.p.: 88° C.

C₁₁ H₁₁ N₃ O₂ S

Elemental analysis: calculated: C 53.0 H 4.45 N 16.9 found: C 53.0 H4.22 N 16.6

EXAMPLE 48

3-Phenylpropyl 3-(1H-imidazol-4-yl )propyl sulphoxide

0.5 g of potassium carbonate in 40 ml of dichloromethane are added to 2mmol of the compound obtained in Example 46 and the mixture is stirredfor 30 min. 2.5 mmol of chloroperbenzoic acid in 20 ml ofdichloromethane are slowly added to the suspension and the mixture isstirred for 2 h at room temperature. The suspension is filtered andpurification is carried out by chromatography. The title compound isrecrystallized in the hydrogenmaleate form from ethanol/diethyl ether.

C₁₅ H₂₀ N₂ OS.C₄ H₄ O₄.0.5H₂ O (401.5) M.p.: 128°-130° C. yield: 60%

Elemental analysis: calculated: C 56.8 H 6.28 N 6.98 found: C 56.8 H6.10 N 6.88

EXAMPLE 49

1-(1H-Imidazol-4-yl)-7-phenylheptan-4-one

5 mmol of 4-(1-(triphenylmethyl)imidazol-4-yl)-butanenitrile areintroduced into a solution of 3-phenyl-5 propylmagnesium bromide in 300ml of diethyl ether and 100 ml of tetrahydrofuran and the mixture isbrought to reflux for 6 h. Hydrolysis is carried out with an ammoniumchloride solution, the organic phase is separated and the aqueous phaseis stirred with dichloromethane. The combined and concentrated organicphases are brought to boiling point for 2 h in a 2N aqueous/alcohol(ethanol/water) hydrochloric acid solution. The ethanol is removed undervacuum, filtration is carried out and basification is carried out. Thetitle compound is stirred in dichloromethane and recrystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₆ H₂₀ N2O.C₄ H₄ O₄.0.5H₂ O (381.4) M.p.: 129° C. yield: 25%

Elemental analysis: calculated: C 63.0 H 6.61 N 7.34 found: C 62.6 H6.53 N 7.86

EXAMPLE 50

1-(1H-Imidazol-4-yl)-7-phenylheptan-4-ol

1 mmol of the compound obtained in Example 49 is introduced into asuspension of 10 mmol of lithium aluminium hydride in 30 ml of diethylether and 10 ml of dioxane and the mixture is stirred overnight.Hydrolysis is carried out with a 2N sodium hydroxide solution and theprecipitate is washed with dichloromethane. The organic phases arecombined and concentrated. The title compound is recrystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₆ H₂₂ N₂ O.C₄ H₄ O₄.H₂ O (392.5) M.p.: 87° C. yield: 40%

Elemental analysis: calculated: C 61.2 H 7.19 N 7.14 found: C 61.6 H6.83 N 7.36

EXAMPLE 51

N-Cyano-N'- 3-(1H-imidazol-4-yl)propyl!-N"-cyclohexylmethylguanidine

5 mmol of diphenyl N-cyanocarbonimidate are stirred with 5 mmol ofcyclohexylmethylamine in 20 ml of acetonitrile for 2 h at roomtemperature. 5 mmol of 3-(1H-imidazol-4-yl)propanamine are then addedand the mixture is brought to reflux for 8 h. The solution isconcentrated under vacuum until dryness and the residue taken up in 5%acetic acid and washed with diethyl ether. After having been basified,the solution is extracted several times with dichloromethane. Thecombined and concentrated organic phases are purified by chromatography.The title compound is obtained, after concentration, in the form of adry foam from diethyl ether.

C₁₅ H₂₄ N₆.0.25H₂ O (292.9) M.p.: about 103° C. yield: 45%

Elemental analysis: calculated: C 61.5 H 8.43 N 28.7 found: C 61.5 H8.49 N 28.3

EXAMPLE 52

N-Ethoxycarbonyl-N'-3-(1H-imidazol-4-yl)propyl!-N"-cyclohexylmethylguanidine

The preparation is carried out as in Example 51 with diphenylN-(ethoxycarbonyl)carbonimidate. The title compound is crystallized fromdiethyl ether.

C₁₇ H₂₉ N₅ O₂ (335.5) M.p.: 118°-119° C. yield: 45%

Elemental analysis: calculated: C 60.9 H 8.71 N 20.9 found: C 60.7 H8.82 N 20.5

EXAMPLE 53

N-(1,1-dimethylethoxycarbonyl)-N'-3-(1H-imidazol-4-yl)propyl!-N"-cyclohexylmethylguanidine

The preparation is carried out as in Example 51 with diphenylN-(1,1-dimethylethoxycarbonyl)carbonimidate. The title compound iscrystallized from diethyl ether.

C₁₉ H₃₃ N₅ O₂ (363.5) M.p.: 137° C. yield: 55%

Elemental analysis: calculated: C 62.8 H 9.15 N 19.3 found: C 62.8 H9.51 N 19.2

EXAMPLE 54

N- 3-(1H-Imidazol-4-yl)propyl!-N'-cyclohexylmethylguanidine

1.5 mmol of the compound obtained in Example 52 are brought to refluxfor 30 min in 15 ml of 1N hydrochloric acid and are then concentrated todryness. The residual dry form is crystallized from diethyl ether.

C₁₄ H₂₅ N₅.2HCl.H₂ O (354.3) M.p.: 76° C. yield: 95%

Elemental analysis: calculated: C 47.5 H 8.25 N 19.8 found: C 47.7 H8.26 N 19.5

EXAMPLE 55

3-(1H-Imidazol-4-yl)propyl N-benzoylcarbamate

5 mmol of 3-(1H-imidazol-4-yl)propanol hydrochloride in 10 ml ofacetonitrile are maintained at reflux for 2 h with 5 mmol of benzoylisocyanate. After evaporation under vacuum, the title compound isstirred in water and filtered.

C₁₄ H₁₅ N₃ O₃.0.25H₂ O (227.8) M.p.: 150° C. yield: 80%

Elemental analysis: calculated: C 60.5 H 5.62 N 15.1 found: C 60.4 H5.44 N 15.2

EXAMPLE 56

3-(1H-Imidazol-4-yl)propyl N-(cyclobutylmethyl)carbamate

The preparation is carried out as in Example 23 with cyclobutylmethylisocyanate. The title compound is extracted from water withdichloromethane and crystallized in the hydrogenmaleate form fromethanol/diethyl ether. C₁₂ H₁₉ N₃ O₂.C₄ O₄.0.25H₂ O (357.9) M.p.: 94° Cyield: 80%

Elemental analysis: calculated: C 53.7 H 6.62 N 11.7 found: C 53.9 H67.2 N 11.8

EXAMPLE 57

3-(1H-Imidazol-4-yl)propyl N-(cyclopropylmethyl)carbamate

The preparation is carried out as in Example 23 with cyclopropylmethylisocyanate. The title compound is extracted from water withdichloromethane and crystallized in the hydrogenmaleate form fromethanol/diethyl ether.

C₁₁ H₁₇ N₃ O₂.C₄ H₄ O₄.0.5H₂ O (348.4) M.p.: 93° C. yield: 50%

Elemental analysis: calculated: C 51.7 H 6.36 N 12.1 found: C 51.8 H6.25 N 11.9

EXAMPLE 58

3-(1H-Imidazol-4-yl)propyl (R)-(+)-N-(1-phenylethyl)carbamate

The preparation is carried out as in Example 23 with(R)-(+)-1-phenylethyl isocyanate. The title compound is extracted fromwater with dichloromethane, purified by chromatography and crystallizedin the hydrogenmaleate form from ethanol/diethyl ether.

C₁₅ H₁₉ N₃ O₂.C₄ H₄ O₄.0.25H₂ O (393.9) M.p.: 105° C. yield: 50%

Elemental analysis: calculated: C 57.9 H 6.01 N 10.7 found: C 57.9 H5.88 N 10.6

EXAMPLE 59

3-(1H-Imidazol-4-yl)propyl (S)-(-)-N-(1-phenylethyl)carbamate

The preparation is carried out as in Example 23 with(S)-(-)-1-phenylethyl isocyanate. The title compound is extracted fromwater with dichloromethane, purified by. chromatography and crystallizedin the hydrogenmaleate form from ethanol/diethyl ether.

C₁₅ H₁₉ N₃ O₂.C₄ H₄ O₄.0.25H₂ O (393.9) M.p.: 105° C. yield: 50%

Elemental analysis: calculated: C 57.9 H 6.01 N 10.7 found: C 58.1 H6.01 N 10.7

EXAMPLE 60

3-(1H-Imidazol-4-yl)propyl N-cyclohexylcarbamate

The preparation is carried out as in Example 23 with cyclohexylisocyanate and 5 mmol of triethylamine while leaving for 4 h at roomtemperature. The title compound is extracted from water withdichloromethane and crystallized in the hydrogenmaleate form fromethanol/diethyl ether.

C₁₃ H₂₁ N₃ O₂.C₄ H₄ O₄.0.25H₂ O (371.9) M.p.: 76° C. yield: 60%

Elemental analysis: calculated: C 54.9 H 6.91 N 11.3 found: C 54.9 H6.91 N 11.4

EXAMPLE 61

3-(1H-Imidazol-4-yl)propyl N-phenylcarbamate

The preparation is carried out as in Example 57 with phenyl isocyanate.The title compound is extracted from water with dichloromethane andcrystallized in the hydrogenmaleate form from ethanol/diethyl ether.

C₁₃ H₁₅ N₃ O₂.C₄ H₄ O₄.0.25H₂ O (365.9) M.p.: 115° C. yield: 70%

Elemental analysis: calculated: C 55.8 H 5.37 N 11.5 found: C 55.7 H5.28 N 11.5

EXAMPLE 62

3-(1H-Imidazol-4-yl)propyl N-(4-methylphenyl)carbamate

The preparation is carried out as in Example 23 with 4-methylphenylisocyanate. The title compound is stirred with water, filtered andcrystallized in the hydrogenmaleate form from ethanol/diethyl ether.

C₁₄ H₁₇ N₃ O₂.C₄ H₄ O₄.0.25H₂ O (379.9) M.p.: 138°-140° C. yield:85%

Elemental analysis: calculated: C 56.9 H 5.70 N 11.1 found: C 57.2 H5.67 N 11.1

EXAMPLE 63

3-(1H-Imidazol-4-yl)propyl N-(4-trifluoromethylphenyl)carbamate

The preparation is carried out as in Example 23 with4-trifluoromethylphenyl isocyanate. The title compound is stirred withwater, filtered and crystallized in the hydrogenmaleate form fromethanol/diethyl ether.

C₁₄ H₁₄ N₃ O₂ F₃.C₄ H₄ O₄.0.25H₂ O (433.9) M.p.: 129° C. yield: 85%

Elemental analysis: calculated: C 49.8 4.30 N 9.69 found: C 50.0 4.18 N9.74

EXAMPLE 64

3-(1H-Imidazol-4-yl)propyl N-(3-trifluoromethylphenyl)carbamate

The preparation is carried out as in Example 23 with3-trifluoromethylphenyl isocyanate. The title compound is stirred withwater, filtered and crystallized in the hydrogenmaleate form fromethanol/diethyl ethyl.

C₁₄ H₁₄ N₃ O₂ F₃.C₄ H₄ O₄.0.25H₂ O (433.9) M.P.: 128° C. yield: 85%

Elemental analysis: calculated: C 49.8 H 4.30 N 9.69 found: C 49.8 H4.17 N 9.53

EXAMPLE 65

3-(1H-Imidazol-4-yl)propyl N-(2trifluoromethylphenyl) carbamate

The preparation is carried out as in Example 23 with2-trifluoromethylphenyl isocyanate. The title compound is stirred withwater, filtered and crystallized in the hydrogenmaleate form fromethanol/diethyl ether.

C₁₄ H₁₄ N₃ O₃ F₃.C₄ H₄ O₄.0.25H₂ O (433.90) M.p.: 83° C. yield: 85%

Elemental analysis: calculated: C 49.8 H 4.30 N 9.69 found: C 50.2 H4.29 N 9.55

EXAMPLE 66

2-(1H-Imidazol-4-yl)ethyl N-(2-phenylethyl)carbamate

The preparation is carried out as in Example 23 with 2-phenylethylisocyanate and 2-(1H-imidazol-4-yl)ethanol. The title compound isextracted from water with dichloromethane, purified by chromatographyand crystallized in the hydrogenmaleate form from ethanol/diethyl ether.

C₁₄ H₂₇ N₃ O₂.C₄ H₄ O₄.0.25H₂ O (379.9) M.p.: 145° C. yield: 65%

Elemental analysis: calculated: C 56.9 H 5.70 N 11.1 found: C 56.9 H5.63 N 10.9

EXAMPLE 67

3-(1H-Imidazol-4-yl )propyl N-(4-nitrobenzyl )carbamate

The preparation is carried out as in Example 23 with 4-nitrobenzylisocyanate. The title compound extracted from water withdichloromethane, purified by chromatography and crystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₄ H₁₆ N₄ O₄.C₄ H₄ O₄. 0.25H₂ O (424.9) M.p.: 128°-129° C. yield: 30%

Elemental analysis: calculated: C 50.9 H 4.86 N 13.2 found: C 50.9 H4.76 N 13.2

EXAMPLE 68

3-(1H-Imidazol-4-yl)propyl N-(4-aminobenzyl)carbamate

2 mmol of the compound obtained in Example 67 are hydrogenated in 10 mlof methanol with 40 mg of palladium-on-charcoal (10%) with hydrogen.After absorption of the calculated amount of hydrogen, the solution isfiltered, concentrated and purified by chromatography. The titlecompound obtained is crystallized in the hydrogenmaleate form fromethanol/diethyl ether.

C₁₄ H₁₈ N₄ O₂.C₄ H₄ O₄.0.25H₂ O (394.9) M.p: 118° C. yield: 60%

Elemental analysis: calculated: C 54.8 H 5.74 N 14.2 found: C 54.8 H5.68 N 14.1

EXAMPLE 69

3-(1H-Imidazol-4-yl)propyl N-(3-nitrophenyl)carbamate

The preparation is carried out as in Example 23 with 3-nitrophenylisocyanate. The title compound is extracted from water withdichloromethane, purified by chromatography and crystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₃ H₁₄ N₄ O₄.C₄ H₄ O₄.0.25H₂ O (410.9) M.p.: 162° C. yield: 55%

Elemental analysis: calculated: C 49.7 H 4.54 N 13.6 found: C 49.5 H4.37 N 13.4

EXAMPLE 70

N- 2-(1H-Imidazol-4-yl)ethyl!-N-methyl-4-cyclohexylbutanamide

The preparation is carried out, as in Example 7, with2-(1H-imidazol-4-yl)-N-methylethylamine as amine component. The titlecompound is extracted from water with diethyl ether and recrystallizedin the hydrogenmaleate form from ethanol/diethyl ether.

C₁₆ H₂₇ N₃ O.C₄ H₄ O₄.0.5H₂ O (402.5) M.p.: 93° C. yield: 40%

Elemental analysis: calculated: C 59.68 H 8.01 N 10.44 found: C 59.57 H7.88 N 10.50

EXAMPLE 71

3-Cyclohexylpropyl ester of 3-(1H-imidazol-4-yl)propanoic acid

5 mmol of the methyl ester of 3-(1H-imidazol-4-yl)propanoic acid arebrought to reflux for 1 h in 20 ml of 3-cyclohexylpropanol whileintroducing HCl gas. The solution is taken up in ethyl acetate, washedwith an aqueous potassium carbonate solution and and concentrated. Thetitle compound is crystallized in the hydrogenmaleate form fromacetonitrile/diethyl ether.

C₁₅ H₂₄ N₂ O₂.C₄ H₄ O₄.0.5H₂ O (389.4) M.p.: 126° C yield: 80%

Elemental analysis: calculated: C 58.6 H 7.51 N 7.19 found: C 58.6 H7.34 N 7.46

EXAMPLE 72

3-(1H-Imidazol-4-yl)propyl N-(2-nitrophenyl)carbamate

The preparation is carried out as in Example 23 with 2-nitrophenylisocyanate. The title compound is separated by filtration andcrystallized in the hydrogenmaleate form from ethanol/diethyl ether.

C₁₃ H₁₄ N₄ O₄.HCl.0.25H₂ O (331.2) M.p.: 160° C. yield: 90%

Elemental analysis: calculated: C 47.1 H 4.72 N 16.9 found: C 47.0 H4.73 N 16.7

EXAMPLE 73

3-(1H-Imidazol-4-yl)propyl N-(4-fluorophenyl)carbamate

The preparation is carried out as in Example 23 with 4-fluorophenylisocyanate. The title compound is extracted from water withdichloromethane, purified by chromatography and crystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₃ H₁₄ N₃ O₂ F.C₄ H₄ O₄.0.25H₂ O (383.8) M.p.: 137° C. yield: 70%

Elemental analysis: calculated: C 53.2 H 4.86 N 11.0 found: C 53.5 H4.76 N 11.0

EXAMPLE 74

3-(1H-Imidazol-4-yl)propyl N-(2-phenylethyl)carbamate with 2-phenylethylisocyanate. The title compound is extracted from water withdicloromethane, purified by chromatography and crystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₅ H₁₉ N₃ O₂.C₄ H₄ O₄.0.25H₂ O (393.9) M.p.: 107°-109° C. yield: 65%

Elemental analysis: calculated: C 57.9 H 6.11 N 10.7 found: C 57.8 H6.01 N 10.7

EXAMPLE 75

3-(1H-Imidazol-4-yl)propyl N-(4-fluorobenzyl)carbamate

The preparation is carried out as in Example 23 with 4-fluorobenzylisocyanate. The title compound is extracted from water withdichloromethane, purified by chromatography and crystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₄ H₁₈ N₃ O₃ F.C₄ O₄.0.25H₂ O (397.9) M.p.: 137°-138° C. yield: 60%

Elemental analysis: calculated: C 54.3 H 5.19 N 10.6 found: C 54.3 H5.19 N 10.5

EXAMPLE 76

3-(1H-Imidazol-4-yl)propyl N-(4-chlorophenyl)carbamate

The preparation is carried out as in Example 23 with 4-chlorophenylisocyanate. The title compound is extracted from water withdichloromethane, purified by chromatography and crystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₃ H₁₄ N₃ O₂ Cl.C₄ H₄ O₄.0.25H₂ O (400.3) M.P.: 132° C. yield: 50 %

Elemental analysis: calculated: C 51.0 H 4.66 N 10.5 found: C 51.0 H4.51 N 10.4

EXAMPLE 77

3-(1H-Imidazol-4yl)propyl N-(4-chlorobenzyl)carbamate

The preparation is carried out as in Example 23 with 4-cholorobenzylisocyanato. The title compound is extracted for water withdichloroethane, purified by chromatography and crystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₄ H₁₆ N₃ O₂ Cl.C₄ H₄ O₄.0.25H₂ O (414.3) M.p.: 133°-134° C. yield

Elemental analysis: calculated: C 52.2 H 4.99 N 10.1 found: C 52.4 H4.90 N 10.1

EXAMPLE 78

3-(1H-Imidazol-4-yl)propyl N-(3-iodophenyl)carbamate

The preparation is carried out as in Example 23 with 3-iodophenylisocyanate. The title compound is extracted from water withdichloromethane, purified by chromatography and crystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₃ H₁₄ N₃ O₂ I.C₄ H₄ O₄.0.25H₂ O (491.8) M.p.: 132° C. yield: 60%

Elemental analysis: calculated: C 41.5 H 3.79 N 8.54 found: C 41.9 H3.88 N 8.67

EXAMPLE 79

3-(1H-Imidazol-4-yl)propyl N-(2-iodophenyl)carbamate

The preparation is carried out as in Example 23 with 2-iodophenylisocyanate. The title compound is extracted from water withdichloromethane, purified by chromatography and crystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₃ H₁₄ N₃ O₂ I.C₄ H₄ O₄.0.25H₂ O (491.8) M.p.: 114° C. yield: 50%

Elemental analysis: calculated: C 41.5 H 3.79 N 8.54 found: C 41.3 H3.62 N 8.43

EXAMPLE 80

3-(1H-imidazol-4-yl)propyl N-(4-iodophenyl)carbamate

The preparation is carried out as in Example 23 with 4-iodophenylisocyanate. The title compound is extracted from water withdichloromethane, purified by chromatography and crystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₃ H₁₄ N₃ O₂ I.C₄ H₄ O₄. 0.25H₂ O (491.8) M.p.: 139° C. yield: 55%

Elemental analysis: calculated: C 41.5 H 3.79 N 8.54 found: C 41.7 H3.75 N 8.44

EXAMPLE 81

3-(1H-Imidazol-4-yl)propyl N-(3-phenylpropyl)carbamate

The preparation is carried out as in Example 23 with 3-phenylpropylisocyanate. The title compound is extracted from water withdichloromethane, purified by chromatography and crystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₆ H₂₁ N₃ O₂.C₄ H₄ O₄.0.25H₂ O (407.9) M.p.: 90° C. yield: 60%

Elemental analysis: calculated: C 58.9 H 6.30 N 10.3 found: C 59.1 H6.38 N 10.5

EXAMPLE 82

3-(1H-Imidazol-4-yl)propyl N-(4-trifluoromethylbenzyl)carbamate

The preparation is carried out as in Example 23 with4-trifluoromethylbenzyl isocyanate. The title compound is stirred withwater, separated by filtration and crystallized in the hydrogenmaleateform from ethanol/diethyl ether.

C₁₅ H₁₆ N₃ O₂ F₃.C₄ H₄ O₄.0.25H₂ O (447.9) M.p.: 97° C. yield: 40%

Elemental analysis: calculated: C 51.0 H 4.61 N 9.38 found: C 51.1 H4.45 N 9.04

EXAMPLE 83

3-(1H-Imidazol-4-yl)propyl N-benzyl-N-methylcarbamate

The preparation is carried out as in Example 23 withN-benzyl-N-methylcarbamoyl chloride. The title compound is stirred withwater, separated by filtration and crystallized in the hydrogenmaleateform from ethanol/diethyl ether.

C₁₅ H₁₉ N₃ O₂. C₄ H₄ O₄.0.25H₂ O (393.9) M.p.: 70° C. yield: 15%

Elemental analysis: calculated: C 57.9 H 6.01 N 10.7 found: C 58.2 H6.07 N 10.6

EXAMPLE 84

3-(1H-Imidazol-4-yl)propyl N-benzyl-N-isopropylcarbamate

The preparation is carried out as in Example 23 withN-benzyl-N-isopropylcarbamoyl chloride. The title compound is stirredwith water, separated by filtration and crystallized in thehydrogenmaleate form from ethanol/diethyl ether.

C₁₇ H₂₃ N₃ O₂.C₄ H₄ O₄.0.5H₂ O (426.5) M.p.: 74°-76° C. yield: 30%

Elemental analysis: calculated: C 59.1 H 6.62 N 9.85 found: C 59.4 H6.54 N 9.56

EXAMPLE 85

3-(4-Chlorophenyl)propyl 3-(1H-imidazol-4-yl)propyl ether

The preparation is carried out as in Example 36 with3-(4-chlorophenyl)propyl chloride. The title compound is crystallized inthe hydrogenmaleate form from ethanol/diethyl ether.

C₁₅ H₁₉ N₂ OCl.C₄ H₄ O₄ (394.9) M.p.: 130° C. yield: 50%

Elemental analysis: calculated: C 57.8 H 5.87 N 7.09 found: C 58.2 H6.02 N 7.30

EXAMPLE 86

(4-Chlorophenyl)methyl 3-(1H-imidazol-4-yl)propyl ether

The preparation is carried out as in Example 36 with(4-chlorophenyl)methyl chloride. The title compound is crystallized inthe hydrogenmaleate form from ethanol/diethyl ether.

C₁₃ H₁₅ N₂ OCl.C₄ H₄ O₄ (366.8) M.p.: 109° C. yield: 50%

Elemental analysis: calculated: C 55.7 H 5.22 N 7.64 found: C 55.6 H5.44 N 7.73

EXAMPLE 87

Cyclohexylmethyl (1H-imidazol-4-yl)methyl ether

The preparation is carried out as in Example 36 with cyclohexylmethylchloride and sodium 1-(triphenylmethyl)imidazol-4-yl!methoxide. Thetitle compound is crystallized in the hydrogenmaleate form fromethanol/diethyl ether.

C₁₁ H₁₈ N₂ O.C₄ H₄ O₄.0.25H₂ O (314.5) M.p.: 102° C. yield: 50%

Elemental analysis: calculated: C 56.4 H 8.77 N 7.26 found: C 56.3 H8.96 N 7.19

EXAMPLE 88

3-(4-Fluorophenyl)propyl 3-(1H-imidazol-4-yl)propyl ether

The preparation is carried out as in Example 36 with3-(4-fluorophenyl)propyl chloride. The title compound is crystallized inthe hydrogenmaleate form from ethanol/diethyl ether.

C₁₅ H₁₉ N₂ OF.C₄ H₄ O₄.0.25H₂ O (382.9) M.p.: 118° C. yield: 45%

Elemental analysis: calculated: C 59.6 H 6.19 N 7.32 found: C 59.3 H6.04 N 7.24

EXAMPLE 89

p-Nitrophenyl trans-3-(1H-imidazol-4-yl)-2-propenoate

2 ml (27.5 mmol) of freshly distilled thionyl chloride are added to afinely ground mixture of 1.51 g (10.8 mmol) of p-nitrophenol and 1.5 g(10.8 mmol) of trans-urocanic acid in a round-bottomed flask equippedwith a drying tube containing CaCl₂. The mixture is progressivelybrought to 140° C. After 4 h, the mixture is slowly cooled to roomtemperature. A brown powder is extracted with CHCl₃ / MeOH (150 ml, 2:1)while heating. The undissolved material is separated by filtration andthe filtrate is treated with active charcoal. Concentration is carriedout under vacuum and diethyl ether is added so as to induceprecipitation of a solid (1.96 g; overall crude yield: 61%). The latteris recrystallized from MeOH and the product is washed with diethyl etherin order to remove any trace of p-nitrophenol, giving a crystallinewhite solid, M.p. 220°-222° C.

C₁₂ H₉ N₃ O₄.HCl

Elemental analysis: calculated: C 48.7 H 3.41 N 14.2 C1 12.0 found: C48.4 H 3.48 N 14.2 Cl 11.9

EXAMPLE 90

2-{ 2-(1H-Imidazol-4-yl)ethyl!amino}pyrimidine

A solution of 2.9 g (27 mmol) of 2-chloropyrimidine and of 3 g (27 mmol)of histamine in 30 ml of 2-propanol is brought to reflux for 36 h. Thesolvent is distilled under reduced pressure and the oily residue ischromatographed on a column of silica gel which is eluted withchloroform and methanol (1:1). The pure fractions are combined andevaporated until an oily residue is obtained which, treated with twoequivalents of oxalic acid in absolute ethanol, provides the product inthe form of an oxalate salt (monohydrate). M.p.: 200°-202° C.

C₉ H₁₁ N₅.C₂ H₂ O₄.H₂ O

Elemental analysis: calculated: C 44.4 H 5.08 N 23.6 found: C 44.8 H4.90 N 23.5

EXAMPLE 91

2-{ 2-(1H-Imidazol-4-yl)ethyl!amino}benzothiazole

Mixing is carried out of 1.65 g (9,7 mmol) of 2-chlorobenzothiazole and1.08 g (9.7 mmol) of histamine base in 20 ml of 2-propanol, the mixtureis brought to reflux for 48 h and evaporation is carried out to dryness.The solid residue is stirred in water for 1 h and the pure product iscollected by filtration; M.p. 185°-187° C. (yield 70%). The maleate saltis prepared from absolute ethanol by adding ether. Afterrecrystallization from absolute ethanol, the maleate salt melts at137°-138° C.

C₁₂ H₁₂ N₄ S.C₄ H₄ O₄.

Elemental analysis: calculated: C 53.3 H 4.47 N 15.5 found: C 53.1 H4.64 N 15.2

EXAMPLE 92

2-{ 2-(1H-Imidazol-4-yl)ethyl!amino}pyridine

A solution of 2.40 g (21 mmol) of histamine base and of 3.41 g (21 mmol)of 2-bromopyridine in 5 ml of 4-picoline is brought to reflux for 26 h.The mixture is evaporated under reduced pressure and the oily residue ischromatographed on a column of silica gel, eluted with a mixture ofchloroform and methanol (1%-20%). An ethanol solution of the resultingproduct is treated with maleic acid and then ether to give thedimaleate. The latter is recrystallized from absolute ethanol.

C₁₀ H₁₂ N₄.2.2C₄ H₄ O₄ M.p.: 137°-138° C.

Elemental analysis: calculated: C 49.3 H 4.59 N 12.6 found: C 49.2 H4.76 N 12.8

EXAMPLE 93

2-{ 2-(1H-Imidazol-4-yl)ethyl!amino}-3-nitropyridine

1.14 g (10.2 mmol) of histamine base and 1.62 g (10.2 mmol) of2-chloro-3-nitropyridine are brought to reflux in 5 ml of 2-propanol for3 h. Evaporation of the solvent under reduced pressure and purificationof the solid residue by chromatography on a column of silica gel, elutedwith chloroform containing increasing amounts of methanol (5, 10 and20%), provide the title compound. M.p.: 178°-180° C. (yield 65%;ethanol:water).

C₁₀ H₁₁ N₅ O₂.

Elemental analysis: calculated: C 51.5 H 4.75 N 30.0 found: C 51.6 H4.69 N 30.0

EXAMPLE 94

2-{ 2-(1H-Imidazol-4-yl)ethyl!amino}-5-nitropyridine

2.22 g (14 mmol) of 2-chloro-5-nitropyridine and an equimolar equivalentof histamine base (1.56 g) in 10 ml of 2-propanol are brought to refluxfor 48 h. The reaction mixture is concentrated to dryness and the solidresidue is taken up in water, heated to boiling, cooled and filtered.The filtrate is concentrated to dryness and chromatographed on a columnof silica gel which is eluted with a mixture of chloroform and methanol(5, 10 and 20%). The combined pure fractions are evaporated to drynessand the solid residue is crystallized from absolute ethanol to providethe product. M.p.: 162°-163° C.

C₁₀ H₁₁ N₅ O₂ :

Elemental analysis: calculated: C 51.5 H 4.75 N 30.0 found: C 51.6 H4.70 N 29.8

EXAMPLE 95

2-{ 2-(1H-Imidazol-4-yl)ethyl!amino}thiazole

1.1 g (10 mmol) of histamine base and 1.6 g (10 mmol) of 2-bromothiazoleare brought to reflux in 15 ml of 2-propanol for 96 h. The reactionmixture is concentrated under reduced pressure until an oily residue isobtained which is chromatographed on a column of silica gel with amixture of chloroform and methanol (1, 5 and 20%) as eluent to providean oil. The latter is taken up in absolute ethanol and is treated withoxalic acid (2 molar equivalents). Addition of ether gives the titlecompound in the dioxalate form which, after having been crystallizedfrom 2-propanol, melts at 198°-199° C.

C₈ H₁₀ N₄ S.C₄ H₄ O₈.

Elemental analysis: calculated: C 38.5 H 3.76 N 15.0 found: C 38.3 H3.50 N 14.7

EXAMPLE 96

2-{ 2-(1H-Imidazol-4-yl)ethyl!amino}pyrazine

1 g (8.9 mmol) of histamine and 1.03 g (8.9 mmol) of 2-chloropyrazineare brought to reflux in 20 ml of 2-propanol for 72 h, evaporated andthe crude solid residue is chromatographed through silica gel, usingchloroform/methanol mixtures (1%, 5%, 10% and 20% respectively). Theproduct is converted to the dioxalate in absolute ethanol and additionof ether gives the title compound which is recrystallized from a2-propanol/diethyl ether mixture in the form of a white solid. M.p.:200°-202° C.

EXAMPLE 97

2-{ 2-(1H-Imidazol-4-yl)ethyl!amino}-3,6-dimethylpyrazine

1 g (8.9 mmol) of histamine and 1.28 g (8.9 mmol) of2-chloro-3,6-dimethylpyrazine in 10 ml of 2-propanol are brought toreflux for 3 days, evaporated and the residue is chromatographed on acolumn of silica gel, using mixtures of chloroform and methanol (1, 10and 20% respectively) to give the title compound in the form of an oil.The latter is converted to a monohydrated dioxalate salt which iscrystallized from an isopropanol/ether (1/1) mixture. M.p.: 164°-165° C.

C₁₁ H₁₅ N₅.C₄ H₄ O₈.H₂ O

Elemental analysis: calculated: C 43.4 H 5.09 N 16.9 found: C 43.5 H4.97 N 16.4

EXAMPLE 98

1-{ 2-(1H-Imidazol-4-yl)ethyl!amino}-4-nitrobenzene

1.45 g (13.1 mmol) of histamine and 2.06 g (13.1 mmol) of1-chloro-4-nitrobenzene are brought to reflux in 20 ml of 2-propanol for3 days. The cooled reaction mixture is filtered, evaporated andchromatographed on a first column of silica gel, using achloroform/methanol (99/1) mixture, and then on a second column, using achloroform/methanol (9/1) mixture. The pure fractions were evaporatedand the resulting solid was treated with oxalic acid in ethanol.Addition of ether provided the title compound in the form of an oxalatesalt, M.p.: 185°-186° C.

C₁₁ H₁₂ N₄ O₂.1.25C₂ H₂ O₄

Elemental analysis: calculated: C 47.0 H 4.23 N 16.2 found: C 46.4 H4.02 N 16.4

EXAMPLE 99

2-{ 2-(1H-Imidazol-4-yl)ethyl!amino}-5-trifluoromethylpyridine

A solution of 1 g (8.9 mmol) of histamine base and of 1.63 g (8.9 mmol)of 2-chloro-5-trifluoromethylpyridine in 5 ml of 2-propanol was broughtto reflux for 3 h while stirring. The cooled reaction mixture wasevaporated to dryness under reduced pressure and the solid residue waschromatographed on a column of silica gel, using a mixture of chloroformand methanol (10/1) as eluent. Treatment of an ethanol solution of theproduct with a solution of oxalic acid provides the dioxalatehemihydrate which is crystallized from a 2-propanol/diethyl ether (10/1)mixture, M.p.: 174°-175° C.

C₁₁ H₁₁ F₃ N₄.C₄ H₄ O₈.0.5H₂ O

Elemental analysis: calculated: C 40.5 H 3.62 N 12.6 found: C 40.3 H3.59 N 12.4

EXAMPLE 100

4-{ 2-(1H-Imidazol-4-yl)ethyl!amino}-2-chloropyridine

38 mg (0.34 mmol) of histamine and 55 mg (0.31 mmol) of2-chloro-4-nitropyridine N-oxide in 15 ml of 2-propanol are stirred withpotassium bicarbonate at 21° C. for 3 days. The mixture is then filteredand evaporated. The resulting solid residue is chromatographed on acolumn of silica gel, using a chloroform/methanol (10/1) mixture. Thepure fractions are evaporated under reduced pressure to give the titlecompound which, after crystallization from a 2-propanol/ether (1/1)mixture, melts at 164°-165° C.

C₁₀ H₁₁ ClN₄.0.2H₂ O

Elemental analysis: calculated: C 53.1 H 5.07 N 24.8 Cl 15.7 found: C53.3 H 4.84 N 24.7 Cl 16.1

EXAMPLE 101

2-{ 2-(1H-Imidazol-4-yl)ethyl!amino}-5-carbomethoxypyridine

0.5 g (4.5 mmol) of histamine and 0.77 g (4.5 mmol) of6-chloro-3-carbomethoxypyridine are stirred with potassium bicarbonatein 20 ml of tetrahydrofuran at 21° C. for 24 h and then heated at refluxfor 24 h. The mixture is evaporated and the white solid residue ischromatographed through silica gel, using a chloroform/methanol (4/1)mixture as eluent. The fractions containing the pure product arecombined and evaporated and the resulting oily residue is treated with amethanol solution of oxalic acid. Addition of ether provides the titlecompound in the form of the oxalate salt, M.p.: 209°-210° C.

C₁₂ H₁₄ N₄ O₂.1.7C₂ H₂ O₄

Elemental analysis: calculated: C 46.3 H 4.39 N 14.0 found: C 46.4 H4.65 N 14.0

EXAMPLE 102

2-{ 2-(1H-Imidazol-4-yl)ethyl!amino}-4-nitropyridine N-oxide

42 mg (0.38 mmol) of histamine and 60 mg (34 mmol) of2-chloro-5-nitropyridine N-oxide are stirred with potassium bicarbonatein 2-propanol at 21° C. for 3 days and then evaporated. The resultingsolid residue is chromatographed on a column of silica gel, using achloroform/methanol (10/1) mixture as eluent. The fractions containingthe title compound and the traces of a few impurities are subjected topreparative high performance liquid chromatography to provide theproduct in the form of a trifluoroacetate salt, M.p.: 193°-194° C.

EXAMPLE 103

2-{ 3-(1H-Imidazol-4-yl)propyl!amino}-5-nitropyridine

A solution of 0.158 g (0.97 mmol) of 3-(1H-imidazol-4-yl)propylamine andof 0.154 g (0.97 mmol) of 2-chloro-5-nitropyridine in 10 ml of2-propanol is brought to reflux for 21 h while stirring and evaporatedunder reduced pressure. The resulting residue is chromatographed on acolumn of silica gel, using a chloroform/methanol (1/1) mixture, to givethe title compound in the form of a yellow oil. The latter is treatedwith oxalic acid in heated absolute ethanol to provide the oxalate saltwhich, after crystallization from 2-propanol, melts at 181°-182° C.

C₁₁ H₁₂ N₅ O₂.C₂ H₂ O₄

Elemental analysis: calculated: C 46.3 H 4.48 N 20.8 found: C 46.1 H4.17 N 20.2

EXAMPLE 104

2-{2- (1H-Imidazol-4-yl)methylthio!ethylamino}-5-nitropyridine

3 g (22 mmol) of 4-hydroxymethyl-1H-imidazole hydrochloride and onemolar equivalent of 2-aminoethanethiol (2.2 g) in 45 ml of aqueous HBr(48%) are brought to reflux for 18 h. The dark-red solution is thenevaporated to dryness and the 4- (2-aminoethyl)thiomethyl!-1H-imidazoledihydrobromide solid residue is washed with 30 ml of an absoluteethanol/ether (1/1) mixture (yield=95%), M.p.: 178°-179° C.

A solution of 5 g (15 mmol) of 4- (2-aminoethyl)thiomethyl!-1H-imidazoledihydrobromide in 5 ml of water is basified to a pH of 11 with 4.3 g (31mmol) of K₂ CO₃ in 15 ml of water. Extraction with 2-propanol providesthe amine base which is freed of the inorganic material by subsequentwashing with 2-propanol. 2 g (12.7 mmol) of the amine and 2 g (12.7mmol) of 2-chloro-5-nitropyridine in 20 ml of 2-propanol are brought toreflux for 18 h. On leaving to stand, an orange solid settles and thelatter is collected and chromatographed on a column of silica gel whichis eluted with a mixture of chloroform and methanol (1, 5, 10 and 20%).The combined fractions are concentrated under reduced pressure todryness and the resulting solid is purified by preparative reverse-phasehigh performance liquid chromatography. The product is crystallized fromabsolute ethanol to give pale-yellow crystals, M.p.: 145°-147° C.

C₁₁ H₁₃ N₅ O₂ S

Elemental analysis: calculated: C 47.3 H 4.69 N 25.1 found: C 46.8 H4.51 N 24.6

EXAMPLE 105

2-{ 2-(1H-Imidazol-4-yl)ethyl!amino}-5-aminopyridine

1.54 g (6.6 mmol) of 2-{2-(1H-imidazol-4-yl)-ethyl!amino}-5-nitropyridine in 100 ml of absoluteEtOH containing a few drops of acetic acid and 0.75 g of 10%palladium-on-charcoal are stirred under hydrogen (1.5 bar) at 20° C. for4 h. The catalyst is removed and the solvent is evaporated under reducedpressure. The oxalate salt is prepared by treatment of an ethanolsolution of the product obtained (title compound) with a solution ofoxalic acid in EtOH followed by addition of diethyl ether. The productis recrystallized from EtOH and melts at 178°-179° C. (yield 95%).

C₁₀ H₁₃ N₅.2C₂ H₂ O₄. H₂ O

Elemental analysis: calculated: C 41.9 H 4.77 N 17.5 found: C 41.6 H4.57 N 17.8

EXAMPLE 106

2- (1H-Imidazol-4-yl)methylthio!-5-nitropyridine

A mixture of 0.6 g (3.9 mmol) of 4-chloromethylimidazole and of anequimolar equivalent of thiourea (0.3 g) in 10 ml of ethanol is broughtto reflux for 30 min. 5 ml of ethanol, 20 ml of water and 1.2 molarequivalents of 2-chloro-5-nitropyridine (0.74 g) in 5 ml of hot ethanolare added to this mixture. The light solution is cooled to 0°-10° C. inan ice bath and a solution of 0.49 g of sodium hydroxide in 10 ml ofwater is added dropwise under nitrogen at 0°-10° C. and then the mixtureis stirred for a further 3 h at 21° C. The precipitate is collected,washed with water and chromatographed through silica gel with a mixtureof chloroform and methanol (1°-20%) to give the title compound, M.p.:155°-156° C.

C₉ H₈ N₄ O₂ S containing 2% of inorganic material

Elemental analysis: calculated: C 44.8 H 3.34 N 23.2 found: C 45.1 H3.33 N 23.3

EXAMPLE 107

2-{2- 1H-Imidazol-4-yl!ethylthio}-5-nitropyridine

A hot solution of 0.2 g (1.3 mmol) of 2-chloro-5-nitropyridine in 5 mlof ethanol is added to a solution of 0.2 g (1.1 mmol) of S-{2-1H-imidazol-4-yl!ethyl}isothiourea dihydrobromide in 2 ml of water. Theresulting suspension is stirred under nitrogen. The reaction mixture iscooled to 0°-5° C. and a solution of 4 molar equivalents of sodiumhydroxide (0.16 g) in 2 ml of water is added dropwise under N₂. Thereaction mixture is stirred for 1 h at the same temperature and for 3 hat 21° C. The reaction mixture is evaporated to dryness and the residueis subjected to column chromatography (silica gel) eluted with agradient mixture of chloroform and methanol (1-10%) to provide the titlecompound which is then crystallized from 2-propanol, M.p.: 147°-148° C.

C₁₀ H₁₀ N₄ O₂ S.0.25H₂ O

Elemental analysis: calculated: C 47.1 H 4.15 N 22.0 S 12.6 found: C47.4 H 3.86 N 21.5 S 12.0

EXAMPLE 108

2-{ 2-(1H-Imidazol-4-yl)ethyl!thio}pyridine

0.5 g (4.4 mmol) of 4-(2-hydroxyethyl)-1H-imidazole and 0.49 g (44.4mmol) of 2-mercaptopyridine are brought to reflux in 5 ml of 47% aqueousHBr for 24 h. The solvent is removed azeotropically with isopropanolunder reduced pressure to provide the title compound in the form of adihydrobromide monohydrate salt which, after crystallization fromisopropanol, melts at 189°-190° C.

C₁₀ H₁₁ N₃ S.2HBr.H₂ O

Elemental analysis: calculated: C 31.2 H 3.92 N 10.9 S 8.3 found C 31.6H 3.87 N 11.0 S 8.6

EXAMPLE 109

2-{ 2-(1H-Imidazol-4-yl)ethyl!thio}-1H-imidazole

183 mg (1.1 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride, 110mg (1 mmol) of 2-mercapto-1H-imidazole and 200 mg (3.26 mmol) of solidpotassium hydroxide are brought to reflux in 10ml of 2-propanol for 4 h.The mixture is then evaporated and the semi-solid residue ischromatographed through silica gel, using a chloroform/methanol (5/1)mixture. The resulting product is treated with oxalic acid in ethanol toprovide the title compound in the form of an oxalate salt, M.p.:224-°226° C.

C₈ H₁₀ N₄ S.1.61C₂ H₂ O₄

Elemental analysis: calculated: C 39.7 H 3.92 H 16.5 S 9.45 found: C39.5 H 3.83 N 16.5 S 9.5

EXAMPLE 110

4- 2-(4-Nitrophenoxy)ethyl!-1H-imidazole

2.09 mg (1.5 mmol) of 4-nitrophenol, 251 mg (1.4 mmol) of 4-2-chloroethyl!-1H-imidazole hydrochloride, 475 mg (3 mmol) of potassiumcarbonate and sodium iodide (catalyst) are stirred at 80° C. for 5 daysin 5 ml of dimethylformamide. The reaction mixture is cooled and 100 mlof diethyl ether are added. The precipitate is separated by filtration.The filtrate is evaporated under reduced pressure to give a residuewhich is subjected to column chromatography (using, as first eluent,chloroform and, as second eluent, a 9/10 chloroform/methanol mixture) togive the title compound which, after crystallization from methanol,melts at: 197°-200° C.

C₁₁ H₁₁ N₃ O₃

Elemental analysis: calculated: C 56.7 H 4.75 N 18.0 found: C 56.9 H4.70 N 17.9

EXAMPLE 111

4- 2-(4-Carbomethoxyphenoxy)ethyl!-1H-imidazole

228 mg (1.5 mmol) of methyl 4-hydroxybenzoate, 251 mg (1.5 mmol) of 4-2-chloroethyl!-1H-imidazole hydrochloride, 500 mg (3.6 mmol) ofpotassium carbonate and sodium iodide (catalyst) are stirred at 80° C.for 3 days in 5 ml of dimethylformamide. The reaction mixture is cooledand filtered and the filtrate is evaporated under reduced pressure togive an oily residue which is subjected to column chromatography (using,as first eluent, chloroform and, as second eluent, a 95/5chloroform/methanol mixture). The product is purified by preparativehigh performance liquid chromatography and crystallized from water;M.p.: 116°-118° C.

C₁₃ H₁₄ N₂ O₃.CF₃ CO₂ H.0.3H₂ O

Elemental analysis: calculated: C 49.3 H 4.30 N 7.7 found: C 49.3 H 3.92N 7.6

EXAMPLE 112

4- 2-(4-Cyanophenoxy)ethyl!-1H-imidazole

360 mg (3 mmol) of 4-cyanophenol, 251 mg (1.5 mmol) of 4-2-chloroethyl!imidazole hydrochloride, 500 mg (3.6 mmol) of potassiumcarbonate and sodium iodide (catalyst) are stirred at 80° C. for 5 daysin 5 ml of dimethylformamide. The mixture is cooled and filtered. Thefiltrate is evaporated under reduced pressure to give an oily residue.The unreacted 4-cyanophenol is precipitated with a methanol/diethylether (1/10) mixture. After filtration, the filtrate is evaporated underreduced pressure to give the title compound which is crystallized from amethanol/water (10/3) mixture, M.p.: 181°-183° C.

C₁₂ H₁₁ N₃ O

Elemental analysis: calculated: C 67.6 H 5.20 N 19.7 found: C 67.2 H5.18 N 19.7

EXAMPLE 113

4- 2-(4-Acetylphenoxy)ethyl!-1H-imidazole

816 mg (6 mmol) of 4-hydroxyacetophenone, 251 mg (1.5 mmol) of 4-2-chloroethyl!-1H-imidazole hydrochloride, 500 mg (3.6 mmol) ofpotassium carbonate and sodium iodide (catalyst) are stirred at 80° C.for 5 days in 5 ml of dimethylformamide. The reaction mixture is cooled,filtered and the filtrate is evaporated under reduced pressure to givean oily residue, from which 4-hydroxyacetophenone is extracted withether at pH=1. Subsequent extraction with ethyl acetate at pH=9 givesthe title compound. The latter was treated with oxalic acid in2-propanol to give the oxalate of the title compound which iscrystallized from a methanol/ether (10/1) mixture, M.p.: 178°-182° C.

C₁₃ H₁₄ N₂ O₂.C₂ H₂ O₄

Elemental analysis: calculated: C 56.2 H 5.04 N 8.8 found: C 56.4 H 5.06N 8.9

EXAMPLE 114

4- 2-(4-Ethoxycarbonylphenoxy)ethyl!-1H-imidazole

1.49 g (9 mmol) of ethyl 4-hydroxybenzoate, 251 mg (1.5 mmol) of4-(2-chloroethyl)-1H-imidazole hydrochloride, 500 g (3.6 mmol) ofpotassium carbonate and sodium iodide (catalyst) are stirred at 80° C.for 4 days in 5 ml of dimethylformamide. The reaction mixture is cooledand then filtered. The filtrate is evaporated under reduced pressure togive an oily residue. The excess ethyl 4-hydroxybenzoate is extractedwith ether at pH=1. The aqueous solution is evaporated under reducedpressure to give the title compound. The latter is purified bypreparative high performance chromatography and converted to the oxalatewhich, after crystallization from an isopropanol/ether mixture, melts at160°-164° C.

C₁₄ H₁₆ N₂ O₃.0.8C₂ H₂ O₄

Elemental analysis calculated: C 56.4 H 5.34 N 8.4 found: C 56.4 H 5.29N 8.3

EXAMPLE 115

4- 2-(3-Nitrophenoxy)ethyl!-1H-imidazole

240 mg (60% in oil, 6 mmol) of sodium hydride are added slowly to asolution of 1.67 g (12 mmol) of 3-nitrophenol in 10 ml ofdimethylformamide and the mixture is stirred at room temperature for 1hour. 200 mg (1.2 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochlorideand tetrabutylammonium iodide (catalyst) are added and the mixture isstirred at 80° C. for 3 days. The reaction mixture is cooled and 150 mlof diethyl ether are added. The precipitate is separated by filtrationand the filtrate is evaporated under reduced pressure to give a residuewhich is purified by preparative high performance chromatography. Thetitle compound is converted to the oxalate and crystallized fromethanol, M.p.: 174°-178° C.

C₁₁ H₁₁ N₃ O₃.0.75C₂ H₂ O₄

Elemental analysis: calculated: C 49.9 H 4.19 N 14.0 found: C 50.1 H4.06 N 13.8

EXAMPLE 116

4- 2-(4-Methoxyphenoxy)ethyl!-1H-imidazole

240 mg (60% in oil, 6 mmol) of sodium hydride are slowly added to asolution of 1.48 g (12 mmol) of 4-methoxyphenol in 7 ml ofdimethylformamide and the mixture is stirred at room temperature for 1hour. 200 mg (1.2 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochlorideand tetrabutylammonium iodide (catalyst) are added and the mixture isstirred at 80° C. for 2 days. The reaction mixture is cooled and 150 mlof diethyl ether are added. The precipitate is separated by filtrationand the filtrate is evaporated under reduced pressure to give a residuewhich is purified by preparative high performance chromatography. Thetitle compound is converted to the oxalate and recrystallized fromethanol, M.p.: 178°-181° C. Elemental analysis: calculated: C 55.8 H5.37 N 9.5 found: C 55.9 H 5.40 N 9.6

EXAMPLE 117

4- 2-(4-Propylphenoxy)ethyl!-1H-imidazole

240 mg (60% in oil; 6 mmol) of sodium hydride are slowly added to asolution of 1.63 g (12 mmol) of 4-propylphenol in 10 ml ofdimethylformamide and the mixture is stirred at room temperature for 1hour. 200 mg (1.2 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochlorideand tetrabutylammonium iodide are added and the mixture is stirred at80° C. for 3 days. The reaction mixture is cooled and 150 ml of diethylether are added. The precipitate is separated by filtration and thefiltrate is evaporated under reduced pressure to give a residue which ispurified by preparative high performance chromatography. The titlecompound is converted to the oxalate (from an ethanol/diethyl ethermixture), M.p.: 168°-171° C.

C₁₄ H₁₈ N₂ O.1.1C₂ H₂ O₄

Elemental analysis: calculated: C 59.1 H 6.18 N 8.5 found: C 58.9 H 6.04N 8.5

EXAMPLE 118

4- 2-(4-Bromophenoxy)ethyl!-1H-imidazole

240 mg (60% in oil; 6 mmol) of sodium hydride are slowly added to asolution of 2.07 g (12 mmol) of 4-bromophenol in 10 ml of formamide andthe mixture is stirred at room temperature for 1 hour. 200 mg (1.2 mmol)of 4-(2-chloroethyl)-1H-imidazole hydrochloride and tetrabutylammoniumiodide (catalyst) are added and the mixture is stirred at 80° C for 3days. The reaction mixture is cooled and 150 ml of diethyl ether areadded. The precipitate is separated by filtration and the filtrate isevaporated under reduced pressure to give a residue which is subjectedto column chromatography through silica gel (first eluent ethyl acetateand second eluent 95/5 ethyl acetate/methanol). The title compound ispurified by preparative high performance chromatography and thenconverted to the oxalate which, after crystallization from anethanol/diethyl ether mixture, melts at 162°-165° C.

C₁₁ H₁₁ BrN₂ O.1.1C₂ H₂ O₄

Elemental analysis: calculated: C 43.3 H 3.63 N7.7 found: C 43.2 H 3.52N7.7

EXAMPLE 119

4- 2-(3,5-Dichlorophenoxy)ethyl!-1H-imidazole

288 mg (60% in oil, 7.2 mmol) of sodium hydride are added to a solutionof 2.34 g (14.4 mmol) of 3,5-dichlorophenol in 4 ml of dimethylformamidewhile cooling in an ice bath. The mixture is stirred at room temperaturefor 1 hour under nitrogen. 200 mg (1.20 mmol)4-(2-chloroethyl)-1H-imidazole hydrochloride and tetrabutylammoniumiodide (catalytic amount) are then added. The mixture is heated at 80°C. for 3 days and then the solvent is evaporated under reduced pressure.

The remaining oily residue is taken up in dichloromethane and dried overanhydrous magnesium sulphate. The solvent is evaporated and the residueis chromatographed on a column of silica gel (10/1dichloromethane/methanol) to remove the excess 3,5-dichlorophenol. Themixture of the compounds obtained after column chromatography isseparated by preparative HPLC (30/70 water containing 0.1% TFA/methanolcontaining 0.1% TFA). The product is obtained in the trifluoroacetateform, M.p.: 115°-116° C.

C₁₁ H₁₀ Cl₂ N₂ O.CF₃ COOH

Elemental analysis: calculated: C 42.1 H 2.99 N 7.6 found: C 42.0 H 2.76N 7.3

EXAMPLE 120

4- 2-(2,3,4,5,6-Pentafluorophenoxy)ethyl!-1H-imidazole

240 mg (60% in oil, 6 mmol) of sodium hydride are added to a solution of2.2 g (12 mmol) of 2,3,4,5,6-pentafluorophenol in 4 ml ofdimethylformamide while cooling in an ice bath. The mixture is stirredat room temperature for 1 hour under nitrogen. 200 mg (1.2 mmol) of4-(2-chloroethyl)-1H-imidazole hydrochloride and tetrabutylammoniumiodide (catalytic amount) are then added. The mixture is heated at 80°C. for 3 days and then the solvent is evaporated under reduced pressure.

The remaining oily residue is taken up in dichloromethane and the excess2,3,4,5,6-pentafluorophenol is extracted with an aqueous sodiumbicarbonate solution. The dichloromethane is evaporated and the titlecompound obtained is converted to the oxalate form by treatment inisopropanol. The isopropanol is evaporated and the compound is dissolvedin ethanol and treated with decolouring active charcoal. The product isobtained after filtration followed by precipitation with diethyl ether,M.p.: 163°-164° C.

C₁₁ H₇ F₅ N₂ O.1.2C₂ H₂ O₄ 0.2H₂ O

Elemental analysis: calculated: C 41.3 H 2.53 N 7.2 found: C 40.9 H 2.09N 7.7

EXAMPLE 121

4- 2-(4-Trifluoromethylphenoxy)ethyl!-1H-imidazole

15 ml of freshly distilled tetrahydrofuran, 340 mg (2.1 mmol) of4-trifluoromethylphenol and 550 mg (2.1 mmol) of triphenylphosphine areadded under nitrogen to 708 g (2 mmol) of1-triphenylmethyl-4-(2-hydroxyethyl)-1H-imidazole. The resulting mixtureis cooled and stirred for 5 min. 66 mg (2.1 mmol) of diethylazodicarboxylate in 10 ml of tetrahydrofuran are then slowly added.Stirring is continued at room temperature for 2 hours under nitrogen.The solvent is then evaporated under reduced pressure and the residue ischromatographed on a column of silica gel, using diethyl ether as theeluent, to give 1-triphenylmethyl-4-2-(4-trifluoromethylphenoxy)ethyl!-1H-imidazole.

A solution of 640 mg (1.28 mmol) of 1-triphenylmethyl-4-2-(4-trifluoromethylphenoxy)ethyl!-1H-imidazole in 2 ml oftetrahydrofuran and 5 ml of 2N hydrochloric acid is heated at 70° C. for2 hours. The tetrahydrofuran is then evaporated under reduced pressureand the residue extracted with diethyl ether. The aqueous solution isbasified with potassium carbonate and the white solid is filtered andwashed 3 times with water to give the title compound, M.p.: 105°-109° C.

C₁₂ H₁₁ N₂ OF₃

Elemental analysis: calculated: C 56.25 H 4.33 N 10.93 found: C 56.30 H4.33 N 10.67

EXAMPLE 122

4- 2-(4-Ethylphenoxy)ethyl!-1H-imidazole

180 mg (60% in oil; 4.5 mmol) of sodium hydride are slowly added to asolution of 1.1 g (9 mmol) of 4-ethylphenol in 7 ml of dimethylformamideand the mixture is stirred at room temperature for 2 hours. 150 mg (0.9mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride andtetrabutylammonium iodide (catalyst) are added and the mixture isstirred at 80° C. for 3 days. The solvent is concentrated and 50 ml ofdiethyl ether are added. The precipitate is separated by filtration andthe filtrate is evaporated under reduced pressure to give a residuewhich is subjected to column chromatography through silica gel (firsteluent ethyl acetate, second eluent 95/5 ethyl acetate/methanol). Thetitle compound is then purified by preparative chromatography and thenconverted to the oxalate which, after crystallization from anethanol/diethyl ether mixture, melts at 178° C.

C₁₃ H₁₆ N₂ O.0.85C₂ H₂ O₄

Elemental analysis: calculated: C 60.3 H 6.09 N 9.6 found: C 60.3 H 6.00N 9.6

EXAMPLE 123

4- 2-(3-Cyanophenoxy)ethyl!-1H-imidazole

240 mg (60% in oil; 6 mmol) of sodium hydride are added to a solution of1.43 g (12 mmol) of 3-hydroxybenzonitrile in 10 ml of dimethylformamideand the mixture is stirred at room temperature for 1 hour undernitrogen. 200 mg (1.2 mmol ) of 4-(2-chloroethyl )-1H-imidazolehydrochloride and tetrabutylammonium iodide (catalytic amount) are addedand the mixture is heated for 3 hours at 80° C. The solvent isevaporated under reduced pressure and the oily residue is stirred inethanol and filtered. The filtrate is evaporated and the residue ispurified by chromatography on a column of silica gel (first eluentchloroform, second eluent 95/5 chloroform/methanol). The title compoundis converted to the oxalate and crystallized from a 2/1 ethanol/diethylether mixture, M.p.: 189°-190° C.

C₂ H₁₁ N₃ O.C₂ H₂ O₄

Elemental analysis: calculated: C 55.5 H 4.32 N 13.9 found: C 55.4 H4.18 N 13.8

EXAMPLE 124

4- 2-(2-Cyanophenoxy)ethyl!-1H-imidazole

240 mg (60% in oil; 6 mmol) of sodium hydride are added to a solution of1.43 g (12 mmol) of 2-hydroxybenzonitrile in 10 ml of dimethylformamide.The mixture is stirred at room temperature for 1 hour under nitrogen.200 mg (1.2 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride andtetrabutylammonium iodide (catalytic amount) are added and the mixtureis heated at 80° C. for 3 days. The solvent is evaporated under reducedpressure and the oily residue is stirred in ethanol and filtered. Thefiltrate is evaporated and the residue subjected to chromatography on acolumn of silica gel (first eluent chloroform, second eluent 95/5chloroform/methanol). The title compound is converted to the oxalate andcrystallized from an ethanol/diethyl ether (2/1) mixture, M.p.:170°-171° C.

C₁₂ H₁₁ N₃ O.0.95C₂ H₂ O₄

Elemental analysis: calculated: C 55.9 H 4.35 N 14.1 found: C 56.1 H4.25 N 14.1

EXAMPLE 125

4- 2-(2-Naphthyloxy)ethyl!-1H-imidazole

240 mg (60% in oil, 6 mmol) of sodium hydride are added to a solution of1.73 g (12 mmol) of 2-naphthol in 10 ml of dimethylformamide. Themixture is stirred at room temperature for 3 hours under nitrogen. 200mg (1.2 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride andtetrabutylammonium iodide (catalytic amount) are added and the mixtureis heated at 100° C. for 3 days and then the solvent is evaporated underreduced pressure. The excess 2-naphthol is extracted with diethyl etherunder acidic conditions (dilute hydrochloric acid). The aqueous solutionis basified with potassium carbonate and the product is extracted withdiethyl ether. The ethereal extracts are concentrated and the residueobtained is crystallized from a methanol/water (1/2) mixture, M.p.:157°-158° C.

C₁₅ H₁₄ N₂ O.0.1H₂ O

Elemental analysis: calculated: C 75.0 H 5.96 N 11.7 found: C 75.0 H5.79 N 11.7

EXAMPLE 126

4- 2-(1-Naphthyloxy)ethyl!-1H-imidazole

240 mg (60% in oil, 6 mmol) of sodium hydride are added to a solution of1.73 g (12 mmol) of 1-naphthol in 10 ml of dimethylformamide. Themixture is stirred at room temperature for 1 hour under nitrogen. 200 mg(1.2 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride andtetrabutylammonium iodide (catalytic amount) are added. The mixture isheated at 100° C. for 3 days and the solvent is then evaporated underreduced pressure. The remaining oily residue is taken up indichloromethane and an aqueous sodium carbonate solution and treatedwith active charcoal. The dichloromethane solution is separated andevaporated and the remaining residue is chromatographed on a column ofsilica gel (10/1 dichloromethane/methanol) to give the title compound inthe base form. The oxalate is prepared from isopropanol and iscrystallized from ethanol, M.p.: 187°-189° C.

C₁₅ H₁₄ N₂ O.1.75C₂ H₂ O₄

Elemental analysis: calculated: C 64.8 H 5.11 N 9.2 found: C 64.8 H 4.76N 8.9

EXAMPLE 127

4- 2-(4-Benzoylphenoxy)ethyl!-1H-imidazole

240 mg (60% in oil, 6 mmol) of sodium hydride are added to a solution of2.34 g (12 mmol) of 4-hydroxybenzophenone in 10 ml of dimethylformamide.The mixture is stirred at room temperature for 1 hour under nitrogen.200 mg (1.2 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride andtetrabutylammonium iodide (catalytic amount) are then added. The mixtureis heated at 100° C. for 2 days and the solvent is then evaporated underreduced pressure. Dilute hydrochloric acid is added to the oily residueand the excess hydroxybenzophenone is extracted with diethyl ether. Theaqueous solution is basified with potassium carbonate and the product isextracted with diethyl ether. The title compound is converted to thedioxalate. Crystallization from an ethanol/diethyl ether (2/1) mixturegives a pure product, M.p.: 193°-194° C.

C₁₈ H₁₆ N₂ O₂.1.3C₂ H₂ O₄

Elemental analysis: calculated: C 60.4 H 4.58 N 6.8 found: C 60.2 H 4.63N 7.1

EXAMPLE 128

4- 2-(4-Nitrophenylthio)ethyl!-1H-imidazole

200 mg (60% in oil, 5 mmol) of sodium hydride are added to a solution of1.86 g (12 mmol) of 4-nitrothiophenol in 10 ml of dimethylformamide. Themixture is stirred at room temperature for 1 hour under nitrogen. 200 g(1.2 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride andtetrabutylammonium iodide (catalytic amount) are then added. The mixtureis heated for 1 day at 80° C. and then the solvent is evaporated underreduced pressure. The residue is stirred in diethyl ether and filtered.Dilute hydrochloric acid is added to the filtrate and the excess4-nitrothiophenol is removed by extracting with diethyl ether. Theaqueous solution is basified with potassium carbonate and then the titlecompound is extracted with chloroform and crystallized from ethanol,M.p.: 167°-168° C.

C₁₁ H₁₁ N₃ O₂ S

Elemental analysis: calculated: C 53.0 H 4.45 N 16.9 found: C 53.1 H4.41 N 16.8

EXAMPLE 129

4- 3-(4-Fluorophenoxy)propyl!-1H-imidazole

5 ml of freshly distilled tetrahydrofuran, 120 mg (1 mmol) of4-fluorophenol and 270 mg (1 mmol) of triphenylphosphine are added,under nitrogen, to 368 mg (1 mmol) of1-triphenylmethyl-4-(3-hydroxypropyl)-1H-imidazole. The resultingmixture is cooled and stirred for 5 min. 180 mg (1 mmol) of diethylazodicarboxylate in 5 ml of tetrahydrofuran are then slowly added.Stirring is continued at room temperature for 3 days under nitrogen. Thesolvent is then evaporated under reduced pressure and the residue issubjected to chromatography on a column of silica gel, using diethylether as eluent, to give 1-triphenylmethyl-4-3-(4-fluorophenoxy)propyl!-1H-imidazole.

A solution of 147 mg (0.4 mmol) of 1-triphenylmethyl-4-3-(4-fluorophenoxy)propyl!-1H-imidazole in 1 ml of tetrahydrofuran and 2ml of 2N hydrochloric acid is heated at 70° C. for 2 hours. Thetetrahydrofuran is then evaporated under reduced pressure. The aqueoussolution is filtered and basified with potassium bicarbonate. Theproduct is extracted with chloroform and dried over magnesium sulphate.The solvent is evaporated under reduced pressure to give the titlecompound in the form of a white solid, M.p.: 135°-137° C.

C₁₂ H₁₃ N₂ OF.0.07CHCl₃

Elemental analysis: calculated: C 63.4 H 5.76 N 12.25 found: C 63.3 H5.66 N 12.33

EXAMPLE 130

4- 3-(4-Cyanophenoxy)propyl!-1H-imidazole

(a) 1-Triphenylmethyl-4-(3-hydroxypropyl)-1H-imidazole

A solution of 2.0 g (15.85 mmol) of 4-(3-hydroxypropyl)-1H-imidazole and5.5 ml (54.3 mmol) of dry ethylamine in 15.6 ml of dimethylformamide istreated with 4.86 g (17.4 mmol) of triphenylmethyl chloride in 5 ml ofdimethylformamide under nitrogen. The mixture obtained is stirred atroom temperature for 2 hours and is then poured onto 350 g of crushedice. The resulting solid is collected by filtration, washed three timeswith water and purified on a chromatographic column using, as eluent,chloroform and then a chloroform/methanol (1/1) mixture to give1-triphenylmethyl-4-(3-hydroxypropyl)-1H-imidazole, M.p.: 132°-133° C.

(b) 5 ml of freshly distilled tetrahydrofuran and 71 mg (0.6 mmol) oftriphenylphosphine are added, under nitrogen, to 184 mg (0.5 mmol) of1-triphenylmethyl-4-(3-hydroxypropyl)-1H-imidazole. The resultingmixture is cooled and stirred for 5 min. 104 mg (0.6 mmol) of diethylazodicarboxylate in 3 ml of tetrahydrofuran are then slowly added andstirring is continued at room temperature for 3 hours under nitrogen.The solvent is then evaporated under reduced pressure and the residue ischromatographed on a column of silica gel (first eluent petroleumether/diethyl ether (1/1); second eluent diethyl ether) to give1-triphenylmethyl-4- 3-(4-cyanophenoxy)propyl!-1H-imidazole, M.p.:187°-188° C.

C₁₂ H₂₇ N₃ O.0.3H₂ O

Elemental analysis: calculated: C 81.5 H 5.82 N 8.9 found: C 81.2 H 5.41N 8.8

(c) A solution of 96 mg (0.2 mmol) of 1-triphenylmethyl-4-3-(4-cyanophenoxy)propyl!-1H-imidazole in 2 ml of tetrahydrofuran and 5ml of 2N hydrochloric acid is heated at 70° C. for 6 hours. Thetetrahydrofuran is then evaporated under reduced pressure and theresidue extracted with diethyl ether. The aqueous solution is basifiedwith potassium carbonate and the product is extracted with chloroformand dried over magnesium sulphate. The solvent is then evaporated underreduced pressure to give the title compound in the form of a white solidwhich is crystallized from an ethanol/ether (1/2) mixture, M.p.:194°-195° C.

C₁₃ H₁₃ N₃ O.0.1H₂ O

Elemental analysis: calculated: C 68.2 H 5.81 N 18.3 found: C 68.3 H5.51 N 18.1

EXAMPLE 131

- 3-(4-Trifluoromethylphenoxy)propyl!-1H-imidazole

(a) 5 ml of tetrahydrofuran, 129 mg (0.8 mmol) of4-trifluoromethylphenol and 209 mg (0.8mmol) of triphenylphosphine areadded, under nitrogen, to 280 mg (0.76 mmol) of1-triphenylmethyl-4-(3-hydroxypropyl)-1H-imidazole. The resultingmixture is stirred for 5 min. 139 mg (0.8 mmol) of diethylazodicarboxylate in 5 ml of tetrahydrofuran are then slowly added.Stirring is continued at room temperature for 3 hours under nitrogen.The solvent is then evaporated and the residue is then chromatographedon a column of silica gel (first eluent petroleum ether containingincreasing amounts of diethyl ether up to 100%) to give the monohydrateof 1-triphenylmethyl-4- 3-(4-trifluoromethylphenoxy)propyl!-1H-imidazolewhich is crystallized from ethanol, M.p.: 150°-151° C.

C₃₂ H₂₇ FN₂ O.1.1H₂ O

Elemental analysis: calculated: C 72.2 H 5.33 N 5.3 found: C 72.1 H 5.44N 5.2

(b) A solution of 260 mg (0.5 mmol) of 1-triphenylmethyl-4-3-(4-trifluoromethylphenoxy)propyl!-1H-imidazole in 2 ml oftetrahydrofuran and 5 ml of 2N hydrochloric acid is heated at 70° C. for6 hours. The organic solvent is then evaporated under reduced pressureand the resulting residue is washed with diethyl ether. The aqueoussolution is basified with potassium carbonate and the title compound isextracted with diethyl ether. The extract is dried over magnesiumsulphate and the solvent is evaporated under reduced pressure to givethe title compound in the form of a white solid. The latter is convertedinto the oxalate which is crystallized from an ethanol/diethyl ethermixture, M.p.: 201°-204° C.

C₁₃ H₁₃ F₃ N₂ O.1.1C₂ H₂ O₄

Elemental analysis: calculated: C 49.4 H 4.15 N 7.6 found: C 49.7 H 3.79N 7.5

The compounds of the preceding examples are collated in the followingTable I.

                                      TABLE I                                     __________________________________________________________________________    Example                                                                            Chain A X          Chain B                                                                             Y                                               __________________________________________________________________________    1    CH.sub.2                                                                              NHCO       (CH.sub.2).sub.4                                                                       ##STR29##                                    2    (CH.sub.2).sub.3                                                                      NHCO       (CH.sub.2).sub.2                                                                       ##STR30##                                    3    (CH.sub.2).sub.3                                                                      NHCO       (CH.sub.2).sub.2                                                                       ##STR31##                                    4    (CH.sub.2).sub.3                                                                      NHCO       (CH.sub.2).sub.2                                                                       ##STR32##                                    5    (CH.sub.2).sub.3                                                                      NHCO       CH.sub.2 O                                                                             ##STR33##                                    6    (CH.sub.2).sub.3                                                                      NHCO       CH.sub.2                                                                               ##STR34##                                    7    (CH.sub.2).sub.3                                                                      NHCO       (CH.sub.2).sub.3                                                                       ##STR35##                                    8    (CH.sub.2).sub.3                                                                      NHCO       (CH.sub.2).sub.2                                                                       ##STR36##                                    9    (CH.sub.2).sub.3                                                                      NHCO       CH.sub.2 CH                                                                            ##STR37##                                    10   (CH.sub.2).sub.3                                                                      NHCO       (CH.sub.2).sub.2                                                                       ##STR38##                                    11   (CH.sub.2).sub.3                                                                      NHCO       (CH.sub.2).sub.2                                                                      (CH.sub.2).sub.2CH.sub.3                      12   (CH.sub.2).sub.3                                                                      NHCO       (CH.sub.2).sub.2                                                                      (CH.sub.2).sub.3CH.sub.3                      13   (CH.sub.2).sub.3                                                                      NHCO       (CH.sub.2).sub.2                                                                      (CH.sub.2).sub.4CH.sub.3                      14   (CH.sub.2).sub.3                                                                      NHCO       (CH.sub.2).sub.2                                                                       ##STR39##                                    15   (CH.sub.2).sub.3                                                                      NHCO       CH.sub.2CH(CH.sub.3)                                                                   ##STR40##                                    16   (CH.sub.2).sub.3                                                                      NHCO       (CH.sub.2).sub.2                                                                       ##STR41##                                    17   (CH.sub.2).sub.4                                                                      NHCO       CH.sub.2                                                                               ##STR42##                                    18   (CH.sub.2).sub.4                                                                      NHCO       (CH.sub.2).sub.2                                                                       ##STR43##                                    19                                                                                  ##STR44##                                                                            NHCO       (CH.sub.2).sub.2                                                                       ##STR45##                                    20   (CH.sub.2).sub.2                                                                      CONH       (CH.sub.2).sub.3                                                                       ##STR46##                                    21   (CH.sub.2).sub.2                                                                      NHCS       (CH.sub.2).sub.3                                                                       ##STR47##                                    22   (CH.sub.2).sub.3                                                                      NHCS       (CH.sub.2).sub.2                                                                       ##STR48##                                    23   (CH.sub.2).sub.3                                                                      NHCONH     CH.sub.2                                                                               ##STR49##                                    24   (CH.sub.2).sub.3                                                                      OCO        (CH.sub.2).sub.2                                                                       ##STR50##                                    25   (CH.sub.2).sub.3                                                                      OCO        --                                                                                     ##STR51##                                    26   (CH.sub.2).sub.3                                                                      OCO        --                                                                                     ##STR52##                                    27   (CH.sub.2).sub.3                                                                      OCO        --                                                                                     ##STR53##                                    28   (CH.sub.2).sub.3                                                                      OCO        --                                                                                     ##STR54##                                    29   (CH.sub.2).sub.3                                                                      OCO        (CH.sub.2).sub.2                                                                       ##STR55##                                    30   (CH.sub.2).sub.3                                                                      OCO        --                                                                                     ##STR56##                                    31   (CH.sub.2).sub.3                                                                      OCO        (CH.sub.2).sub.3                                                                       ##STR57##                                    32   (CH.sub.2).sub.3                                                                      OCO        CH.sub.2                                                                               ##STR58##                                    33   (CH.sub.2).sub.3                                                                      OCO        (CH.sub.2).sub.3                                                                       ##STR59##                                    34   (CH.sub.2).sub.3                                                                      OCONH      CH.sub.2                                                                               ##STR60##                                    35   (CH.sub.2).sub.3                                                                      OCONH      CH.sub.2                                                                               ##STR61##                                    36   (CH.sub.2).sub.3                                                                      O          (CH.sub.2).sub.3                                                                       ##STR62##                                    37   (CH.sub.2).sub.3                                                                      O          (CH.sub.2).sub.3                                                                       ##STR63##                                    38   (CH.sub.2).sub.3                                                                      O          (CH.sub.2).sub.3                                                                       ##STR64##                                    39   (CH.sub.2).sub.3                                                                      O          (CH.sub.2).sub.3                                                                       ##STR65##                                    40   (CH.sub.2).sub.3                                                                      O          CH.sub.2                                                                               ##STR66##                                    41   (CH.sub.2).sub.3                                                                      O          CH.sub.2                                                                               ##STR67##                                    42   (CH.sub.2).sub.3                                                                      O          (CH.sub.2).sub.4                                                                       ##STR68##                                    43                                                                                  ##STR69##                                                                            NHCO       (CH.sub.2).sub.2                                                                       ##STR70##                                    44                                                                                  ##STR71##                                                                            NHCO       (CH.sub.2).sub.2                                                                       ##STR72##                                    45   (CH.sub.2).sub.3                                                                      O          (CH.sub.2).sub.3                                                                       ##STR73##                                    46   (CH.sub.2).sub.3                                                                      S          (CH.sub.2).sub.3                                                                       ##STR74##                                    47   CH.sub.2                                                                              S          CH.sub.2                                                                               ##STR75##                                    48   (CH.sub.2).sub.3                                                                       ##STR76## (CH.sub.2).sub.3                                                                       ##STR77##                                    49   (CH.sub.2).sub.3                                                                       ##STR78## (CH.sub.2).sub.3                                                                       ##STR79##                                    50   (CH.sub.2).sub.3                                                                       ##STR80## (CH.sub.2).sub.3                                                                       ##STR81##                                    51   (CH.sub.2).sub.3                                                                       ##STR82## CH.sub.2                                                                               ##STR83##                                    52   (CH.sub.2).sub.3                                                                       ##STR84## CH.sub.2                                                                               ##STR85##                                    53   (CH.sub.2).sub.3                                                                       ##STR86## CH.sub.2                                                                               ##STR87##                                    54   (CH.sub.2).sub.3                                                                       ##STR88## CH.sub.2                                                                               ##STR89##                                    55   (CH.sub.2).sub.3                                                                       ##STR90## --                                                                                     ##STR91##                                    56   (CH.sub.2).sub.3                                                                       ##STR92## CH.sub.2                                                                               ##STR93##                                    57   (CH.sub.2).sub.3                                                                       ##STR94## CH.sub.2                                                                               ##STR95##                                    58   (CH.sub.2).sub.3                                                                       ##STR96##                                                                                ##STR97##                                                                             ##STR98##                                    59   (CH.sub.2).sub.3                                                                       ##STR99##                                                                                ##STR100##                                                                            ##STR101##                                   60   (CH.sub.2).sub.3                                                                       ##STR102##                                                                              --                                                                                     ##STR103##                                   61   (CH.sub.2).sub.3                                                                       ##STR104##                                                                              --                                                                                     ##STR105##                                   62   (CH.sub.2).sub.3                                                                       ##STR106##                                                                              --                                                                                     ##STR107##                                   63   (CH.sub.2).sub.3                                                                       ##STR108##                                                                              --                                                                                     ##STR109##                                   64   (CH.sub.2).sub.3                                                                       ##STR110##                                                                              --                                                                                     ##STR111##                                   65   (CH.sub.2).sub.3                                                                       ##STR112##                                                                              --                                                                                     ##STR113##                                   66   (CH.sub.2).sub.2                                                                       ##STR114##                                                                              (CH.sub.2).sub.2                                                                       ##STR115##                                   67   (CH.sub.2).sub.3                                                                       ##STR116##                                                                              CH.sub.2                                                                               ##STR117##                                   68   (CH.sub.2).sub.3                                                                       ##STR118##                                                                              CH.sub.2                                                                               ##STR119##                                   69   (CH.sub.2).sub.3                                                                       ##STR120##                                                                              --                                                                                     ##STR121##                                   70   (CH.sub.2).sub.2                                                                       ##STR122##                                                                              (CH.sub.2).sub.3                                                                       ##STR123##                                   71   (CH.sub.2).sub.2                                                                      COO        (CH.sub.2).sub.3                                                                       ##STR124##                                   72   (CH.sub.2).sub.3                                                                       ##STR125##                                                                              --                                                                                     ##STR126##                                   73   (CH.sub.2).sub.3                                                                       ##STR127##                                                                              --                                                                                     ##STR128##                                   74   (CH.sub.2).sub.3                                                                       ##STR129##                                                                              (CH.sub.2).sub.2                                                                       ##STR130##                                   75   (CH.sub.2).sub.3                                                                       ##STR131##                                                                              CH.sub.2                                                                               ##STR132##                                   76   (CH.sub.2).sub.3                                                                       ##STR133##                                                                              --                                                                                     ##STR134##                                   77   (CH.sub.2).sub.3                                                                       ##STR135##                                                                              CH.sub.2                                                                               ##STR136##                                   78   (CH.sub.2).sub.3                                                                       ##STR137##                                                                              --                                                                                     ##STR138##                                   79   (CH.sub.2).sub.3                                                                       ##STR139##                                                                              --                                                                                     ##STR140##                                   80   (CH.sub.2).sub.3                                                                       ##STR141##                                                                              --                                                                                     ##STR142##                                   81   (CH.sub.2).sub.3                                                                       ##STR143##                                                                              (CH.sub.2).sub.3                                                                       ##STR144##                                   82   (CH.sub.2).sub.3                                                                       ##STR145##                                                                              CH.sub.2                                                                               ##STR146##                                   83   (CH.sub.2).sub.3                                                                       ##STR147##                                                                              CH.sub.2                                                                               ##STR148##                                   84   (CH.sub.2).sub.3                                                                       ##STR149##                                                                              CH.sub.2                                                                               ##STR150##                                   85   (CH.sub.2).sub.3                                                                      O          (CH.sub.2).sub.3                                                                       ##STR151##                                   86   (CH.sub.2).sub.3                                                                      O          CH.sub.2                                                                               ##STR152##                                   87   (CH.sub.2).sub.3                                                                      O          CH.sub.2                                                                               ##STR153##                                   88   (CH.sub.2).sub.3                                                                      O          (CH.sub.2).sub.3                                                                       ##STR154##                                   89   CHCH    COO        --                                                                                     ##STR155##                                   90   (CH.sub.2).sub.2                                                                      NH         --                                                                                     ##STR156##                                   91   (CH.sub.2).sub.2                                                                      NH         --                                                                                     ##STR157##                                   92   (CH.sub.2).sub.2                                                                      NH         --                                                                                     ##STR158##                                   93   (CH.sub.2).sub.2                                                                      NH         --                                                                                     ##STR159##                                   94   (CH.sub.2).sub.2                                                                      NH         --                                                                                     ##STR160##                                   95   (CH.sub.2).sub.2                                                                      NH         --                                                                                     ##STR161##                                   96   (CH.sub.2).sub.2                                                                      NH         --                                                                                     ##STR162##                                   97   (CH.sub.2).sub.2                                                                      NH         --                                                                                     ##STR163##                                   98   (CH.sub.2).sub.2                                                                      NH         --                                                                                     ##STR164##                                   99   (CH.sub.2).sub.2                                                                      NH         --                                                                                     ##STR165##                                   100  (CH.sub.2).sub.2                                                                      NH         --                                                                                     ##STR166##                                   101  (CH.sub.2).sub.2                                                                      NH         --                                                                                     ##STR167##                                   102  (CH.sub.2).sub.2                                                                      NH         --                                                                                     ##STR168##                                   103  (CH.sub.2).sub.3                                                                      NH         --                                                                                     ##STR169##                                   104  CH.sub.2 SCH.sub.2 CH.sub.2                                                           NH         --                                                                                     ##STR170##                                   105  (CH.sub.2).sub.2                                                                      NH         --                                                                                     ##STR171##                                   106  CH.sub.2                                                                              S          --                                                                                     ##STR172##                                   107  (CH.sub.2).sub.2                                                                      S          --                                                                                     ##STR173##                                   108  (CH.sub.2).sub.2                                                                      S          --                                                                                     ##STR174##                                   109  (CH.sub.2).sub.2                                                                      S          --                                                                                     ##STR175##                                   110  (CH.sub.2).sub.2                                                                      O          --                                                                                     ##STR176##                                   111  (CH.sub.2).sub.2                                                                      O          --                                                                                     ##STR177##                                   112  (CH.sub.2).sub.2                                                                      O          --                                                                                     ##STR178##                                   113  (CH.sub.2).sub.2                                                                      O          --                                                                                     ##STR179##                                   114  (CH.sub.2).sub.2                                                                      O          --                                                                                     ##STR180##                                   115  (CH.sub.2).sub.2                                                                      O          --                                                                                     ##STR181##                                   116  (CH.sub.2).sub.2                                                                      O          --                                                                                     ##STR182##                                   117  (CH.sub.2).sub.2                                                                      O          --                                                                                     ##STR183##                                   118  (CH.sub.2).sub.2                                                                      O          --                                                                                     ##STR184##                                   119  (CH.sub.2).sub.2                                                                      O          --                                                                                     ##STR185##                                   120  (CH.sub.2).sub.2                                                                      O          --                                                                                     ##STR186##                                   121  (CH.sub.2).sub.2                                                                      O          --                                                                                     ##STR187##                                   122  (CH.sub.2).sub.2                                                                      O          --                                                                                     ##STR188##                                   123  (CH.sub.2).sub.2                                                                      O          --                                                                                     ##STR189##                                   124  (CH.sub.2).sub.2                                                                      O          --                                                                                     ##STR190##                                   125  (CH.sub.2).sub.2                                                                      O          --                                                                                     ##STR191##                                   126  (CH.sub.2).sub.2                                                                      O          --                                                                                     ##STR192##                                   127  (CH.sub.2).sub.2                                                                      O          --                                                                                     ##STR193##                                   128  (CH.sub.2).sub.2                                                                      S          --                                                                                     ##STR194##                                   129  (CH.sub.2).sub.3                                                                      O          --                                                                                     ##STR195##                                   130  (CH.sub.2).sub.3                                                                      O          --                                                                                     ##STR196##                                   131  (CH.sub.2).sub.3                                                                      O          --                                                                                     ##STR197##                               

The compounds of formula IA or IB in accordance with the inventioncause, in vitro, blocking of the H₃ histaminergic receptors whichcontrol the release and the formation of cerebral histamine and, invivo, an increase in the rate of renewal of cerebral histamine, effectswhich in particular establish a psychotropic action.

Antagonism of the stimulation by histamine of the central H₃ receptorswas revealed by virtue of the method described by Arrang et al. (Nature,1983, 302, 832-837). This method requires rat cerebral cortex sectionsand has made possible the pharmacological characterization of the H₃receptors (Nature, 1987, 327, 117-123).

Exogenous histamine (at the concentration of 1 μM) inhibits release byapproximately 50%. This effect is progressively reversed in the presenceof H₃ antagonists, such as the compounds of the invention, added inincreasing concentrations. The concentration of the latter for which theeffect of exogenous histamine is reduced by half (IC₅₀) is determinedand the apparent inhibition constant (Ki) is then calculated accordingto Cheng and Prusoff (Biochim. Pharmacol., 1973, 22, 3099-3108), takinginto account the 50% effective concentration of histamine (EC=0.1 μM).The results are collated in the following Table II.

                  TABLE II                                                        ______________________________________                                        APPARENT DISSOCIATION CONSTANTS (Ki) OF VARIOUS                               DERIVATIVES OF THE INVENTION AS ANTAGONISTS OF                                HISTAMINE ON THE H.sub.3 RECEPTORS OF THE BRAIN OF THE RAT.                          Example No.                                                                           Ki (nM)                                                        ______________________________________                                               2       49                                                                    7       59                                                                    15      35                                                                    19      42                                                                    22      11                                                                    24       3                                                                    36      20 ± 8                                                             38      15 ± 4                                                             45      17 ± 3                                                             49      20                                                                    55      52                                                                    61      14 ± 8                                                             67      22                                                                    73      24 ± 4                                                             83      18                                                                    85      13 ± 4                                                             88       7 ± 2                                                             91      38                                                                    107     35                                                                    110     35 ± 6                                                             112      9 ± 5                                                             117     19 ± 9                                                             125      90 ± 27                                                           130     12 ± 3                                                             131     14 ± 6                                                      ______________________________________                                    

The compounds of the invention cause, in vivo, after intraperitoneal ororal administration in rats, an increase in the rate of renewal of thecerebral histamine. The latter is estimated either by studying thedecrease in the level of the cerebral histamine after blockage of itssynthesis (Garbarg et al., Europ. Jr. Pharmacol., 164, 1-11, 1989) or bystudying the increase in the level of the catabolite of histamine,telemethylhistamine (Garbarg et al., J. Neurochem., 53, 1724-1730,1989).

This property of active H3 antagonists generally makes compounds of theinvention useful derivatives in human and veterinary medicine. Theirtherapeutic applications especially relate to the central nervous system(including as psychostimulants). The compounds of formula IA or IB areadvantageously used as an active principle of medicaments which act asan antagonist of H₃ receptors of histamine, of medicaments possessingsedative, sleep regulating, anticonvulsant, psychostimulating, cerebralcirculation modulating, antidepressant or antiulcer effects.

The present invention therefore also relates to the pharmaceuticalcompositions which contain, as active principle, a therapeuticallyeffective amount of one of the compounds of formula IA or IB.

The pharmaceutical composition in accordance with the invention can beadministered to man orally, perlingually, nasally, rectally andparenterally, the active principle being combined with a therapeuticallysuitable excipient or vehicle.

Each unit dose advantageously contains from 0.1 to 100 mg of activeprinciple, it being possible for the doses which can be adminsitereddaily to vary from 0.3 mg to 300 mg of active principle.

Another subject of the invention is the use of the derivatives inaccordance with the invention for the preparation of H₃ antagonistmedicaments according to the abovementioned forms.

The use of the compounds of formulae IA and IB in which

a) X represents --NH--, the chain A the --(CH₂)₂ -- group, the chain Bthe --(CH₂)₂ --O-- group or the group --(CH₂)_(n) --S-- and Y the phenylor p-chlorophenyl group,

b) X represents the --NHCO-- group, the chain A the --(CH₂)₂ -- groupand Y the methyl group (formula IB) or the chain B and Y (formula IA)represent a straight alkylene chain --(CH₂)_(n) --, n being between 1and 4, the --CH₂ --O-- or --CH₂ --S--CH₂ -- groups and a phenyl group,or also the --CH₂ --CH₂ -- or --CH₂ --S--CH₂ -- groups and the diphenylgroup, or also the --(CH₂)₃ -- or --CH₂ --S--CH₂ -- groups and thepyridyl group, or also the --CH₂ --CH₂ -- or --CH₂ --S-- groups and thediphenyl group, or else the --(CH₂)₃ -- group and the imidazolyl orcyclohexyl group,

c) X represents --NHCO--, the chain A the --CH₂ --CH(CH₃)-- group, thechain B the --(CH₂)₃ -- group and Y the phenyl group,

d) X represents --NHCSNH-- --NHCONH--, the chain A the --(CH₂)₂ --group, the chain B the --(CH₂)₂ -- group and Y the phenyl group,

whose antagonist properties of the H₃ receptors of histamine weredisclosed during a symposium which was held at Budapest in August 1988("10th International Symposium on Medicinal Chemistry") and morerecently at Noordwijkerhout (July 1990), is not, however, claimed.

Another subject of the invention is the use of the derivatives inaccordance with the invention for preparing medicaments possessing asedative, sleep regulating, anticonvulsant, psychotropic,psychostimulating, cerebral circulation modulating, antidepressant orantiulcer effect.

The invention further relates to a method for the treatment of pre-citedailments according to which a medicament containing a therapeuticallyeffective dose of a compound of general formula IA or IB, optionally incombination with a therapeutically acceptable vehicle or excipient, isadministered.

We claim:
 1. A medicament acting as an antagonist of the H₃ receptors ofhistamine containing a compound selected from the group consisting of acompound of the formula ##STR198## in which A is a hydrocarbon chaincontaining 1 to 6 carbon atoms uninterrupted or interrupted by aheteroatom selected from the group consisting of --S--, --O-- and--NH--; X is selected from the group consisting of oxygen, sulfur,--CO--, --NH--, --NHCO--, --N(alkyl)CO--, NHCONH--, --NHCS--, --O--CO--,--CO--O--, --OCONH--, --OCON(alkyl)--, --OCONH-- --CONH--,--CON(alkyl)--, --SO--, --CHOH-- and --NR--C(═NR")--NR'--; R and R' arehydrogen or lower alkyl; and R" is selected from the group consisting ofhydrogen, cyano and --COY₁, Y₁ is alkoxy; B is selected from the groupconsisting of --(CH₂)_(n) --, n is an integer from 0 to 5, a branchedalkylene of 2 to 8 carbon atoms uninterrupted or interrupted by at leastone oxygen or sulfur, --(CH₂)_(n) --O--, and --(CH₂)_(n') --S--, wheren' is an integer of 1 or 2; Y is selected from the group consisting ofalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms,bicycloalkyl, cycloalkenyl, aryl, 5- or 6-membered heterocycle selectedfrom the group consisting of pyridyl, N-oxide-pyridyl, pyrimidinyl, andpyrazinyl unsubstituted or substituted with at least one member of thegroup consisting of --NO₂, --CF₃, --CH₃, --NH₂, halogen, --COOCH₃,imidazolyl, thiazolyl, and a bicyclic formed by a heterocycle as definedabove to which a phenyl ring is fused;with the proviso that, when X is--NH-- and A is a straight saturated hydrocarbon chain containing 1 to 6carbon atoms, B cannot be a straight alkylene chain and Y cannot bephenyl or imidazolyl; with the proviso that, when X is --NH-- and A is--(CH₂)₂ --, B and Y cannot simultaneously be --(CH₂)₂ --O-- or--(CH₂)_(n) --S-- and phenyl or p-chlorophenyl; with the proviso thatwhen X is --NH-- and A is a straight saturated hydrocarbon chain of 1 to6 carbon atoms, Y cannot be substituted or unsubstituted aryl (formulaIB), and when X is --NH-- and A is --CH₂ -- in formula IA, B and Ycannot simultaneously be --CH₂ -- and 2,6-dimethylphenyl; with theproviso that when X is --NH-- and A is --(CH₂)₂ --, B and Y cannotsimultaneously be --CH(C₁ -C₃ alkyl)--CH₂)_(n) -- (n=1 to 4) and methylor substituted or unsubstituted phenyl in formula IA and Y cannot be--(CH₂)6-- in the formula IB; with the proviso that, when X is--NHCONH-- and A is a straight saturated hydrocarbon chain of 1 to 6carbon atoms, B and/or Y cannot be alkyl, and Y cannot be aryl; with theproviso that, when X is --NHCO-- and A is --(CH₂)₂ --, Y in formula IBcannot be methyl or substituted cyclohexyl, or Y cannot bepara-nitrophenyl or para-amino-phenyl, B and Y in formula IA cannotsimultaneously be --(CH₂)_(n) --, n being an integer of 1 to 6, --CH₂--O--, or --CH₂ S--CH₂ -- and phenyl, or --CH₂ --CH₂ -- or --CH₂--S--CH₂ -- and diphenyl or --(CH₂)₃ -- or --CH₂ --S--CH₂ and pyridyl,or --CH₂ --CH₂ -- or --CH₂ --S-- and diphenyl or --(CH₂)₃ -- andimidazolyl or cyclohexyl; with the proviso that, when X is --NHCO-- andA is --CH₂ --CH(CH₃)--, B and Y cannot simultaneously be --(CH₂)₃ -- andphenyl; with the proviso that, when X is --NHCONH-- and A is --(CH₂)₂, Band Y cannot simultaneously be --CH₂ --CH₂ -- and phenyl; with theproviso that, when X is oxygen and A is --CH₂ --, Y in formula IB cannotbe substituted phenyl; with the proviso that, when X is --CO-- and A is--(CH₂)₂ --, Y in formula IB cannot be substituted or unsubstitutedaryl; with the proviso that, when X is --CO-- and A is methylene, B andY cannot simultaneously be --C(CH₃)₂ --(CH₂)_(n) -- (n=0 or 1) andsubstituted or unsubstituted aryl; with the proviso that, when X is--CONH-- and A is --(CH₂)₂ --, Y in formula IB cannot be substituted orunsubstituted phenyl; with the proviso that, when X is--NH--C(═NCN)--NH--, A and B are hydrocarbon chains of 2 to 5 carbonatoms interrupted or uninterrupted by S or O, Y cannot be pyridyl,imidazolyl, or thiazolyl; with the proviso that, when X is--NH--C(═NCN)--NH-- and A is --CH₂ --S--(CH₂)₂ --, Y in formula IBcannot be methyl; with the proviso that, when X is --NH--C(═NH)--NH--, Ycannot be alkyl or aryl; with the proviso that, when X is--NH--C(═NH)--NH--, A is --(CH₂)_(n) -- (n=2 or 3), Y cannot be pyridyl,imidazolyl, benzimidazolyl or quinolyl in formula IA; with the provisothat, when X is --NH--C--(═NCOY₁)--NH-- and A is hydrocarbon of 2 to 5carbon atoms interrupted by 0 or S, Y cannot be alkyl; with the provisothat, when X is --NH--C(--NCOY₁)--NH--, A is --(CH₂)_(n) -- (n=2 or 3)and B is --(CH₂)_(n) -- (n=2 to 5) or a branched alkylene chain of 3 to6 carbon atoms optionally interrupted or uninterrupted by oxygen orsulfur, or --(CH₂)₂ --O-- or (CH₂)₂ --S--, Y cannot be substituted orunsubstituted aryl or pyridyl, imidazolyl, benzimidazolyl or quinolyl;with the proviso that, when X is --NH--C(=NCOY₁)--NH--, A is --(CH₂)_(n)-- (n=2 or 3), Y in formula IB cannot be pyridyl; with the proviso that,when X is NH and Y is alkyl, A is neither --(CH₂)₂ -- nor --(CH₂)₃ --;and a pharmaceutically acceptable salt, hydrate, hydrated salt,polymorphic crystalline structures of the tautomeric forms thereof, inthe presence or absence of a therapeutically acceptable vehicle orexcipient.
 2. The medicament of claim 1 wherein A is --(CH₂)_(n) -- andn is an integer from 0 to
 6. 3. The medicament of claim 2 wherein n is 1to
 4. 4. The medicament of claim 2 wherein A is alkylene substitutedwith at least one methyl or ethyl.
 5. The medicament of claim 1 whereinY is selected from the group consisting of cyclopentyl, cyclohexyl andbicycloalkyl.
 6. The medicament of claim 1 wherein Y is phenylsubstituted with at least one member of the group consisting of halogen,lower alkyl, --CF₃, --CN, --COCH₃, --COOR₁, --COR₁, --OR₁, --COOH, --NO₂##STR199## R₁ is alkyl and R₂ and R₃ are individually hydrogen or loweralkyl.
 7. The medicament of claim 1 wherein Y is benzothiazolyl.
 8. Themedicament of claim 1 wherein A is a saturated hydrocarbon chaininterrupted by a sulfur.
 9. A medicament acting as an antagonist of theH₃ receptors of histamine containing a compound of the formula##STR200## wherein A is a hydrocarbon of 2 to 6 carbon atoms, X isoxygen and Y is phenyl unsubstituted or substituted by at least onemember of the group consisting of halogen, lower alkyl, --CF₃ --CH,--COCH₃, --COOR₁, --OR₁, --COR₁, --COOH, --NO₂ and ##STR201## R₁ islower alkyl and R₂ and R₃ are hydrogen or lower alkyl or apharmaceutically acceptable salt, hydrate, hydrated salt, polymorphiccrystalline structures or the tautomeric forms thereof, in the presenceor absence of a therapeutically acceptable vehicle or excipient.
 10. Themedicament of claim 9 wherein A is ethylene or propylene.
 11. Amedicament acting as an antagonist of H₃ receptors of histaminecontaining a compound selected from the group consisting of ##STR202##wherein A is a hydrocarbon of 1to 6 carbon atoms uninterrupted orinterrupted by a heteroatom selected from the group consisting ofoxygen, sulfur and --NH--; X is selected from the group consisting of--OCO--, --COO--, --OCOHN--, --OCON(alkyl)--, and --OCOHN--CO--; B isselected from the group consisting of --(CH₂)_(n) --, n is an integerfrom 0 to 5, a branched alkylene of 2 to 8 carbon atoms uninterrupted orinterrupted by at least one oxygen or sulfur, --(CH₂)_(n') --O-- and--(CH₂)_(n), --S-- wherein n' is an integer of 1 or 2; Y is selectedfrom the group consisting of alkyl of 1 to 8 carbon atoms, cycloalkyl of3 to 6 carbon atoms, bicycloalkyl, cycloalkenyl, aryl, 5- or 6-memberedheterocycle selected from the group consisting of pyridyl,N-oxide-pyridyl, pyrimidinyl and pyrazinyl unsubstituted or substitutedwith at least one member of the group consisting of --NO₂ --, --CF₃,--CH₃, --NH₂, halogen, --COOCH₃, imidazolyl, thiazolyl, and a bicyclicformed by a heterocycle as defined above to which a phenyl ring is fusedand a pharmaceutically acceptable salt, hydrate, hydrated salt,polymorphic crystalline structures, or tautomeric forms thereof, in thepresence or absence of a therapeutically acceptable vehicle orexcipient.
 12. A medicament acting as an antagonist of the H₃ receptorsof histamine containing a compound selected from the group consisting of##STR203## wherein A is a hydrocarbon of 1 to 6 carbon atomsuninterrupted or interrupted by a heteroatom selected from the groupconsisting of oxygen, sulfur, and --NH--; X is selected from the groupconsisting of sulfur, oxygen, --N(alkyl)CO--, --NHCS--, --CON(alkyl)--,--SO--, and --CHOH--; B is selected from the group consisting of--(CH₂)_(n), n is an integer from 0 to 5, a branched alkylene of 2 to 8carbon atoms uninterrupted or interrupted by at least one member of thegroup consisting of oxygen, sulfur, --(CH₂)_(n) '--O-- and --(CH₂)_(n)'--S--, where n' is an integer of 1 or 2; Y is selected from the groupconsisting of alkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to 6 carbonatoms, cycloalkyl, cycloalkenyl, aryl 5- or 6-membered heterocycleselected from the group consisting of pyridyl, n-oxide-pyridyl,pyrimidinyl, and pyrazinyl unsubstituted or substituted with at leastone member of the group consisting of --NO₂ --, --CF₃, --CH₃, --NH₂,halogen, --COOCH₃, imidazolyl, thiazolyl, and a bicyclic formed by saidheterocycle as defined above to which a phenyl ring is fused providedthat when X is oxygen and A is --CH₂ --, Y in formula I_(B) cannot besubstituted phenyl, and a pharmaceutically acceptable salt, hydrate,hydrated salt, polymorphic crystalline structures, or tautomeric formsthereof, in the presence or absence of a therapeutically acceptablevehicle or excipient.
 13. A medicament acting as an antagonist of the H₃receptors of histamine containing a compound of the formula ##STR204##wherein A is a hydrocarbon of 1 to 6 carbon atoms, uninterrupted orinterrupted by a heteroatom selected from the group consisting ofoxygen, sulfur and nitrogen; X is ##STR205## R and R' are hydrogen orlower alkyl; R" is selected from the group consisting of hydrogen,cyano, and --COY₁, Y₁ is alkoxy; B is selected from the group consistingof --(CH)_(n) --, n is an integer from 0 to 5, a branched alkylene of 2to 8 carbon atoms uninterrupted or interrupted by at least one oxygen orsulfur, --(CH₂)_(n) '--O-- and --(CH₂)_(n), --S-- where n' is an integerof 1 or 2; Y is selected from the group consisting of cycloalkyl of 3 to6 carbon atoms, bicycloalyl, cycloalkenyl, pyrimidinyl and pyrazinylunsubstituted and substituted with at least one member of the groupconsisting of --NO₂, --CF₃, --CH₃, --NH₂, halogen and --COOCH₃ with theproviso that when X is --NH--C(NCN)--NH--, A and B are hydrocarbonchains of 2 to 5 carbon atoms interrupted or uninterrupted by S or O, Ycannot be pyridyl, imidazolyl, or thiazolyl;with the proviso that, whenX is --NH--C(═NCN)--NH-- and A is --CH₂ -- S--(CH₂)₂ --, Y in formula IBcannot be methyl; with the proviso that, when X is --NH--C(═NH)--NH--, Ycannot be alkyl or aryl; with the proviso that, when X is--NH--C(═NH)--NH--, A is --(CH₂)_(n) (n=2 or 3), Y cannot be pyridyl,imidazolyl, benzimidazolyl or quinolyl in formula IA; with the provisothat, when X is --NH--C--(═NCOY₁)--NH-- and A is hydrocarbon of 2 to 5carbon atoms interrupted or uninterrupted by O or S, Y cannot be alkyl;with the proviso that, when X is --NH--C--(NCOY₁)--NH--, A is--(CH₂)_(n) -- (n=2 or 3) and B is --(CH₂)_(n) -- (n=2 to 5) or abranched alkylene chain of 3 to 6 carbon atoms optionally interrupted oruninterrupted by oxygen or sulfur, or --(CH₂)₂ --O-- or (CH₂)--S--, Ycannot be substituted or unsubstituted aryl or pyridyl, imidazolyl,benzimidazolyl or quinolyl; with the proviso that, when X is--NH--C(═NCOY₁)--NH--, A is --(CH₂)_(n) -- (n=2 or 3), Y in formula IBcannot be pyridyl; and a pharmaceutically acceptable salt, hydrate,hydrated salt, polymorphic crystalline structures, or tautomeric formsthereof, in the presence or absence of a therapeutically acceptablevehicle or excipient.
 14. A medicament acting as an antagonist of the H₃receptors of histamine containing a compound according to claim 1selected from the group consistingof:N-((1H-Imidazol-4-yl)methyl)-5-phenylpentanamide,N-(3-(1H-Imidazol-4-yl)propyl)-3-phenylpropanamide,N-(3-(1H-Imidazol-4-yl)propyl)-3cyclohexylpropanamide,N-(3-(1H-Imidazol-4-yl)propyl)-3-cyclopentylpropanamide,N-(3-(1H-Imidazol-4-yl)propyl)-2-(4-chlorophenoxy)acetamide,N-(3-(1H-Imidazol-4-yl)propyl)-2-cyclohexylacetamide,N-(3-(1H-Imidazol-4-yl)propyl)-4-cyclohexylbutanamide,N-(3-(1H-Imidazol-4-yl)propyl)-4-methylpentanamide,N-(3-(1H-Imidazol-4-yl)propyl)-3,3-diphenylpropanamide,N-(3-(1H-Imidazol-4-yl)propyl)-3-(bicyclo- 2.2.1!hept-2-yl)propanamide,N-(3-(1H-Imidazol-4-yl)propyl)hexanamide,N-(3-(1H-Imidazol-4-yl)propyl)heptanamideN-(3-(1H-Imidazol-4-yl)propyl)octanamide,N-(3-(1H-Imidazol-4-yl)propyl)-3-(2-cyclopenten-1-yl)propanamide,(R,S)-(±)-N-(3-(1H-Imidazol-4-yl)propyl)-3-phenylbutanamide,N-(3-(1H-Imidazol-4-yl)propyl)-3-(2-pyrazinyl)propanamide,N-(4-(1H-Imidazol-4-yl)butyl)-2-cyclopentylacetamide,N-(4-(1H-Imidazol-4-yl)butyl)-3-cyclopentylpropanamide,(E)-N-(3-(1H-Imidazol-4-yl)allyl)-3-cyclopentylpropanamide,N-(3-Phenylpropyl)-3-(1H-imidazol-4-yl)propanamide,N-(2-(1H-Imidazol-4-yl)ethyl)-4-cyclohexylbutanethioamide,N-(3-(1H-Imidazol-4-yl)propyl)-3-cyclopentylpropanethioamide,N-Benzyl-N'-(3-(1H-imidazol-4-yl)propyl)urea, 3-(1H-Imidazol-4-yl)propylester of 3-cyclopentylpropanoic acid, 3-(1H-Imidazol-4-yl)propyl esterof benzoic acid, 3-(1H-Imidazol-4-yl)propyl ester of 4-iodobenzoic acid,3-(1H-Imidazol-4-yl)propyl ester of 3-iodobenzoic acid,3-(1H-Imidazol-4-yl)propyl ester of 3-iodo-4-methylbenzoic acid,3-(1H-Imidazol-4-yl)propyl ester of 3-(4-iodophenyl)propanoic acid,3-(1H-Imidazol-4-yl)propyl ester of 4-amino-3,5-diiodobenzoic acid,3-(1H-Imidazol-4-yl)propyl ester of 4-(4-iodophenyl)butanoic acid,3-(1H-Imidazol-4-yl)propyl ester of 2-(4-iodophenyl)acetic acid,3-(1H-Imidazol-4-yl)propyl ester of 4-phenylbutanoic acid,3-(1H-Imidazol-4-yl)propyl N-benzylcarbamate, 3-(1H-Imidazol-4-yl)propylN-(cyclohexylmethyl)carbamate, 3-Cyclohexylpropyl3-(1H-imidazol-4-yl)propyl ether, 3-(3,4-Difluorophenyl)propyl3-(1H-imidazol-4-yl)propyl ether, 3-(4-Bromophenyl)propyl3-(1H-imidazol-4-yl)propyl ether, 3-(3-Trifluoromelthylphenyl)propyl3-(1H-imidazol-4-yl)propyl ether, 1-Naphthylmethyl3-(1H-imidazol-4-yl)propyl ether, (4-Iodophenyl)methyl3-(1H-imidazol-4-yl)propyl ether, 4-Phenylbutyl3-(1H-imidazol-4-yl)propyl ether,(Z)-N-(3-(1H-Imidazol-4-yl)allyl)-3-cyclohexylpropanamide,(R,S)-(±)-N-(3-(1-Imidazol-4-yl)butyl)-3-cyclohexylpropanamide,3-Phenylpropyl 3-(1H-imidazol-4-yl)propyl ether, 3-Phenylpropyl3-(1H-imidazol-4-yl)propyl sulphide, 4-(4-Nitrobenzylthio)methyl!-1H-imidazole, 3-Phenylpropyl3-(1H-imidazol-4-yl)propyl sulphoxide,1-(1H-Imidazol-4-yl)-7-phenylheptan-4-one,1-(1H-Imidazol-4-yl)-7-phenylheptan-4-ol, N-Cyano-N'-3-(1H-imidazol-4-yl)propyl!-N"-cyclohexylmethylguanidine,N-Ethoxycarbonyl-N'-3-(1H-imidazol-4-yl)propyl!-N"-cyclohexylmethylguanidine,N-(1,1-Dimethylethoxycarbonyl)-N'-3-(1H-imidazol-4-yl)propyl!-N"-cyclohexylmethylguanidine, N-3-(1H-Imidazol-4-yl)propyl!-N'-cyclohexylmethylguanidine,3-(1H-imidazol-4-yl)propyl N-benzoylcarbamate,3-(1H-Imidazol-4-yl)propyl N-(cyclobutylmethyl)carbamate,3-(1H-Imidazol-4-yl)propyl -N-(cyclopropylmethyl)carbamate,3-(1H-Imidazol-4-yl)propyl (R)-(+)-N-(1-phenylethyl)carbamate,3-(1H-Imidazol-4-yl)propyl (S)-(-)-N-(1-phenylethyl)carbamate,3-(1H-imidazol-4-yl)propyl N-cyclohexylcarbamate,3-(1H-imidazol-4-yl)propyl N-phenylcarbamate, 3-(1H-Imidazol-4-yl)propyl N-methylphenyl)carbamate, 3-(1H-Imidazol-4-yl)propylN-(4-trifluoromethyl)carbamate, 3-(1H-Imidazol-4-yl)propylN-(3-trifluoromethylphenyl)carbamate, 3-(1H-Imidazol-4-yl)propylN-(2-trifluoromethylphenyl)carbamate, 2-(1H-Imidazol-4-yl)propylN-(2-phenylethyl)carbamate, 3-(1H-Imidazol-4-yl)propylN-(4-nitrobenzyl)carbamate, 3-(1H-Imidazol-4-yl)propylN-(4-aminobenzyl)carbamate, 3-(1H-Imidazol-4-yl)propylN-(3-nitrophenyl)carbamate, N-2-(1H-Imidazol-4-yl)ethyl!-N-methyl-4-cyclohexylbutanamide,3-Cyclohexylpropyl ester of 3-(1H-imidazol-4-yl)propanoic acid,3-(1H-Imidazol-4-yl)propyl N-(2-nitrophenyl)carbamate,3-(1H-Imidazol-4-yl)propyl N-(4-fluorophenyl)carbamate,3-(1H-Imidazol-4-yl)propyl N-(2-phenylethyl)carbamate,3-(1h-Imidazol-4-yl)propyl N-(4-fluorobenzyl)carbamate,3-(1H-Imidazol-4-yl)propyl N-(4-chlorophenyl)carbamate,3-(1H-Imidazol-4-yl)propyl N-(4-chlorobenzyl)carbamate,3-(1H-Imidazol-4-yl)propyl N-(3-iodophenyl)carbamate,3-(1H-Imidazol-4-yl)propyl N-(2-iodophenyl)carbamate,3-(1H-Imidazol-4-yl)propyl N-(4-iodophenyl)carbamate,3-(1H-Imidazol-4-yl)propyl N-(3-phenylpropyl)carbamate,3-(1H-Imidazol-4-yl)propyl N-(4-trifluoromethylbenzyl)carbamate,3-(1H-Imidazol-4-yl)propyl N-benzyl-N-methylcarbamate,3-(1H-Imidazol-4-yl)propyl N-benzyl-N-isopropylcarbamate,3-(4-Chlorophenyl)propyl 3-(1H-imidazol-4-yl)propyl ether,(4-Chlorophenyl)methyl 3-(1H-imidazol-4-yl)propyl ether,Cyclohexylmethyl (1H-imidazol-4-yl)methyl ether,3-(4-Fluorophenyl)propyl 3-(1H-imidazol-4-yl)propyl ether, p-Nitrophenyltrans-3-(1H-imidazol-4-yl)-2-propenoate, 2-{2-(1H-Imidazol-4-yl)ethyl!amino}pyrimidine, 2-{2-(1H-Imidazol-4-yl)ethyl!amino}benzothiazole, 2-{2-(1H-Imidazol-4-yl)ethyl!amino}pyridine, 2-{2-(1H-Imidazol-4-yl)ethyl!amino}-3-nitropyridine, 2-{2-(1H-Imidazol-4-yl)ethyl!amino}-5-nitropyridine, 2-{2-(1H-Imidazol-4-yl)ethyl!amino}thiazole, 2-{2-(1H-Imidazol-4-yl)ethyl!amino}pyrazine, 2-{2-(1H-Imidazol-4-yl)ethyl!amino}-3,6-dimethylpyrazine, 1-{2-(1H-Imidazol-4-yl)ethyl!amino}-4-nitrobenzene, 2-{2-(1H-Imidazol-4-yl)ethyl!amino}-5-trifluoromethylpyridine, 4-{2-(1H-Imidazol-4-yl)ethyl!amino}-2-chloropyridine, 2-{2-(1H-Imidazol-4-yl)ethyl!amino}-5-carbomethoxypyridine, 2-{2-(1H-Imidazol-4-yl)ethyl!amino}-4-nitropyridine-N-oxide, 2-{3-(1H-Imidazol-4-yl)propyl!amino}-5-nitropyridine, 2-{2-(1H-Imidazol-4-yl)methylthio!ethylamino}-5-nitropyridine, 2-{2-(1H-Imidazol-4-yl)ethyl!amino}-5-aminopyridine, 2-(1H-Imidazol-4-yl)methylthio!-5-nitropyridine, 2-{2-1H-Imidazol-4-yl!ethylthio}-5-nitropyridine, 2-{2-(1H-Imidazol-4-yl)ethyl!thio}pyridine, 2-{2-(1H-Imidazol-4-yl)ethyl!thio}-1H-imidazole, 4-2-(4-Nitrophenoxy)ethyl!-1H-imidazole, 4-2-(4-Carbomethoxyphenoxy)ethyl)!-1H-imidazole, 4-2-(4-Cyanophenoxy)ethyl!-1H-imidazole, 4-2-(4-Acetylphenoxy)ethyl!-1H-imidazole, 4-2-(4-Ethoxycarbonylphenoxy)ethyl!-1H-imidazole, 4-2-(3-Nitrophenoxy)ethyl!-1H-imidazole, 4-2-(4-Methoxyphenoxy)ethyl!-1H-imidazole, 4-2-(4-Propylphenoxy)ethyl!-1H-imidazole, 4-2-(4-Bromophenoxy)ethyl!-1H-imidazole, 4-2-(3,5-Dichlorophenoxy)ethyl!-1H-imidazole, 4-2-(2,3,4,5,6-Pentafluorophenoxy)ethyl!-1H-imidazole, 4-2-(4-Ethylphenoxy)ethyl!-1H-imidazole, 4-2-(3-Cyanophenoxy)ethyl!-1H-imidazole, 4-2-(2-Cyanophenoxy)ethyl!-1H-imidazole, 4-2-(2-Naphthyloxy)ethyl!-1H-imidazole, 4-2-(4-Trifluoromethylphenoxy)ethyl!-1H-midazole, 4-2-(1-Naphthyloxy)ethyl!-1H-imidazole, 4-2-(4-Benzoylphenoxy)ethyl!-1H-imidazole, 4-2-(4-Nitrophenylthio)ethyl!-1H-imidazole, 4-3-(4-Cyanophenoxy)propyl!-1H-imidazole, 4-3-(4-Trifluoromethylphenoxy)propyl!-1H-imidazole, in the presence ofpresence or absence of a therapeutically acceptable vehicle orexcipient.